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Endothelial cells (ECs) rely on glycolysis for energy production to maintain vascular homeostasis and the normalization of hyperglycolysis in tumor vessels has recently gained attention as a therapeutic target. We analyzed the TCGA database and found reduced Foxp1 expression in lung carcinoma. Immunostaining demonstrated reduced expression more restricted at tumor vascular ECs. Therefore, we investigated the function and mechanisms of Foxp1 in EC metabolism for tumor angiogenesis required for tumor growth. EC-Foxp1 deletion mice exhibited a significant increase of tumor and retinal developmental angiogenesis and Hif1α was identified as Foxp1 target gene, and Hk2 as Hif1α target gene. The Foxp1-Hif1α-Hk2 pathway in ECs is important in the regulation of glycolytic metabolism to govern tumor angiogenesis. Finally, we used genetic deletion of EC-Hif1α and RGD-peptide nanoparticles EC target delivery of Hif1α/Hk2-siRNAs to knockdown gene expression which reduced the tumor EC hyperglycolysis state and restricted angiogenesis for tumor growth. This study advances our understanding of EC metabolism for tumor angiogenesis, and meanwhile provides evidence for future therapeutic intervention of hyperglycolysis in tumor ECs for suppression of tumor growth.

Intestinal dysbiosis and disrupted bile acid (BA) homeostasis are associated with obesity, but the precise mechanisms remain insufficiently explored. Hepatic protein phosphatase 1 regulatory subunit 3G (PPP1R3G) plays a pivotal role in regulating glycolipid metabolism; nevertheless, its obesity-combatting potency remains unclear. In this study, a substantial reduction was observed in serum PPP1R3G levels in high-body mass index (BMI) and high-fat diet (HFD)-exposed mice, establishing a positive correlation between PPP1R3G and non-12α-hydroxylated (non-12-OH) BA content. Additionally, hepatocyte-specific overexpression of Ppp1r3g (PPP1R3G HOE) mitigated HFD-induced obesity as evidenced by reduced weight, fat mass, and an improved serum lipid profile; hepatic steatosis alleviation was confirmed by normalized liver enzymes and histology. PPP1R3G HOE considerably impacted systemic BA homeostasis, which notably increased the non-12-OH BAs ratio, particularly lithocholic acid (LCA). 16S ribosomal DNA (16S rDNA) sequencing assay indicated that PPP1R3G HOE reversed HFD-induced gut dysbiosis by reducing the Firmicutes/Bacteroidetes ratio and Lactobacillus population, and elevating the relative abundance of Blautia, which exhibited a positive correlation with serum LCA levels. A fecal microbiome transplantation test confirmed that the anti-obesity effect of hepatic PPP1R3G was gut microbiota-dependent. Mechanistically, PPP1R3G HOE markedly suppressed hepatic cholesterol 7α-hydroxylase (CYP7A1) and sterol-12α-hydroxylase (CYP8B1), and concurrently upregulated oxysterol 7-α hydroxylase and Takeda G protein-coupled BA receptor 5 (TGR5) expression under HFD conditions. Furthermore, LCA administration significantly mitigated the HFD-induced obesity phenotype and elevated non-12-OH BA levels. These findings emphasize the significance of hepatic PPP1R3G in ameliorating diet-induced adiposity and hepatic steatosis through the gut microbiota-BA axis, which may serve as potential therapeutic targets for obesity-related disorders.

Abstract Cardiac macrophage contributes to the development of cardiac fibrosis, but factors that regulate cardiac macrophages transition and activation during this process remains elusive. Here we show, by single-cell transcriptomics, lineage tracing and parabiosis, that cardiac macrophages from circulating monocytes preferentially commit to macrophage-to-myofibroblast transition (MMT) under angiotensin II (Ang II)-induced hypertension, with accompanying increased expression of the RNA N6-methyladenosine demethylases, ALKBH5. Meanwhile, macrophage-specific knockout of ALKBH5 inhibits Ang II-induced MMT, and subsequently ameliorates cardiac fibrosis and dysfunction. Mechanistically, RNA immunoprecipitation sequencing identifies interlukin-11 (IL-11) mRNA as a target for ALKBH5-mediated m6A demethylation, leading to increased IL-11 mRNA stability and protein levels. By contrast, overexpression of IL11 in circulating macrophages reverses the phenotype in ALKBH5-deficient mice and macrophage. Lastly, targeted delivery of ALKBH5 or IL-11 receptor α (IL11RA1) siRNA to monocytes/macrophages attenuates MMT and cardiac fibrosis under hypertensive stress. Our results thus suggest that the ALKBH5/IL-11/IL11RA1/MMT axis alters cardiac macrophage and contributes to hypertensive cardiac fibrosis and dysfunction in mice, and thereby identify potential targets for cardiac fibrosis therapy in patients.

ABSTRACT: Mastitis is one of the most frequent and costly diseases affecting dairy cattle. Natural antibodies (immunoglobulins) and cyclophilin A (CyPA), the most abundant member of the family of peptidyl prolyl cis/trans isomerases, in milk may serve as indicators of mastitis resistance in dairy cattle. However, genetic information for CyPA is not available, and knowledge on the genetic and nongenetic relationships between these immune-related traits and somatic cell score (SCS) and milk yield in dairy cattle is sparse. Therefore, we aimed to comprehensively evaluate whether immune-related traits consisting of 5 Ig classes (IgG, IgG1, IgG2, IgA, and IgM) and CyPA in the test-day milk of Holstein cows can be used as genetic indicators of mastitis resistance by evaluating the genetic and nongenetic relationships with SCS in milk. The nongenetic factors affecting immune-related traits and the effects of these traits on SCS were evaluated. Furthermore, the genetic parameters of immune-related traits according to health status and genetic relationships under different SCS environments were estimated. All immune-related traits were significantly associated with SCS and directly proportional. Additionally, evaluation using a classification tree revealed that IgA, IgG2, and IgG were associated with SCS levels. Genetic factor analyses indicated that heritability estimates were low for CyPA (0.08) but moderate for IgG (0.37), IgA (0.44), and IgM (0.44), with positive genetic correlations among Ig (0.25–0.96). We also evaluated the differences in milk yield and SCS of cows between the low and high groups according to their sires' estimated breeding value for immune-related traits. In the high group, IgA had a significantly lower SCS in milk at 7 to 30 d compared with that in the low group. Furthermore, the Ig in milk had high positive genetic correlations between healthy and infected conditions (0.82–0.99), suggesting that Ig in milk under healthy conditions could interact with those under infected conditions, owing to the genetic ability based on the level of Ig in milk. Thus, Ig in milk are potential indicators for the genetic selection of mastitis resistance. However, because only the relationship between immune-related traits and SCS was investigated in this study, further study on the relationship between clinical mastitis and Ig in milk is needed before Ig can be used as an indicator of mastitis resistance.

Abstract Depression is a common and debilitating condition for which effective treatments are needed. Lepidium meyenii Walp (Maca) is a plant with potential medicinal effects in treating depression. Recently, there has been growing interest in plant‐derived extracellular vesicles (EVs) due to their low toxicity and ability to transport to human cells. Targeting the gut–brain axis, a novel strategy for depression management, may be achieved through the use of Maca‐derived EVs (Maca‐EVs). In this study, we successfully isolated Maca‐EVs using gradient ultracentrifugation and characterized their shape, size, and markers (CD63 and TSG101). The in vivo imaging showed that the Dil‐labeled Maca‐EVs crossed the brain–blood barrier and accumulated in the brain. The behavioral tests revealed that Maca‐EVs dramatically recovered the depression‐like behaviors of unpredictable chronic mild stress (UCMS) mice. UCMS mice fecal were characterized by an elevated abundance of g_Enterococcus, g_Lactobacillus, and g_Escherichia_Shigella, which were significantly restored by administration of Maca‐EVs. The effects of Maca‐EVs on the altered microbial and fecal metabolites in UCMS mice were mapped to biotin, pyrimidine, and amino acid (tyrosine, alanine, aspartate, and glutamate) metabolisms, which were closely associated with the serotonin (5‐HT) production. Maca‐EVs were able to increase serum monoamine neurotransmitter levels in UCMS mice, with 5‐HT showing the most significant changes. We further demonstrated that 5‐HT improved the expression of brain‐derived neurotrophic factor, a key regulator of neuronal plasticity, and its subsequent activation of TrkB/p‐AKT signaling by regulating the GTP‐Cdc42/ERK pathway. These findings suggest that Maca‐EVs enhance 5‐HT release, possibly by modulating the gut–brain axis, to improve depression behavior. Our study sheds light on a novel approach to depression treatment using plant‐derived EVs.

Endothelial dysfunction results in chronic vascular inflammation, which is critical for the development of atherosclerotic diseases. Transcription factor Gata6 has been reported to regulate vascular endothelial cell activation and inflammation in vitro. Here, we aimed to explore the roles and mechanisms of endothelial Gata6 in atherogenesis.Endothelial cell (EC) specific Gata6 deletion was generated in the ApoeKO hyperlipidemic atherosclerosis mouse model. Atherosclerotic lesion formation, endothelial inflammatory signaling, and endothelial-macrophage interaction were examined in vivo and in vitro by using cellular and molecular biological approaches. EC-GATA6 deletion mice exhibited a significant decrease in monocyte infiltration and atherosclerotic lesion compared to littermate control mice. Cytosine monophosphate kinase 2 (Cmpk2) was identified as a direct target gene of GATA6 and EC-GATA6 deletion decreased monocyte adherence, migration and pro-inflammatory macrophage foam cell formation through regulation of the CMPK2-Nlrp3 pathway. Endothelial target delivery of Cmpk2-shRNA by intercellular adhesion molecule 2 (Icam-2) promoter-driven AAV9 carrying the shRNA reversed the Gata6 upregulation mediated elevated Cmpk2 expression and further Nlrp3 activation and thus attenuated atherosclerosis. In addition, C–C motif chemokine ligand 5 (Ccl5) was also identified as a direct target gene of Gata6 to regulate monocyte adherence and migration influencing atherogenesis.This study provides direct in vivo evidence of EC-GATA6 involvement in the regulation of Cmpk2-Nlrp3, as well as Ccl5, on monocyte adherence and migration in atherosclerosis development and advances our understanding of the in vivo mechanisms of atherosclerotic lesion development, and meanwhile provides opportunities for future therapeutic interventions.

In vitro culture models that precisely mirror the porcine respiratory epithelium are needed to gain insight into how pathogens and host interact. In this study, a new porcine bronchial epithelial cell line, designated as PBE cells, was established from the respiratory tract of a neonatal pig. PBE cells assumed a cobblestone-epithelial like morphology with close contacts between the cells when they reached confluence. The PBE cell line was characterized in terms of its expression of pattern recognition receptors (PRRs) and its ability to respond to the activation of the Toll-like receptor 3 (TLR3) and TLR4 signaling pathways, which are key PRRs involved in the defense of the respiratory epithelium against pathogens. PBE cells stimulated with poly(I:C) were able to up-regulate the expression of IFN-β, IFN-λ1 (IL-29), IFN-λ3 (IL-28B), the antiviral factors Mx1, OAS1, and PKR, as well as the viral PRRs RIG-1 and MDA5. The expression kinetics studies of immune factors in PBE cells allow us to speculate that this cell line can be a useful in vitro tool to investigate treatments that help to potentiate antiviral immunity in the respiratory epithelium of the porcine host. In addition, poly(I:C) and LPS treatments increased the expression of the inflammatory cytokines TNF-α, IL-6, IL-8, and MCP-1/CCL2 and differentially modulated the expression of negative regulators of the TLR signaling pathways. Then, PBE cells may also allow the evaluation of treatments that can regulate TLR3- and TLR4-mediated inflammatory injury in the porcine airway, thereby protecting the host against harmful overresponses.

Preterm white matter injury (PWMI), characterized by oligodendrocyte precursor cell (OPC) differentiation disorder and dysmyelination, is a prevalent demyelinating disease of the central nervous system in premature infants, necessitating the development of mitigating strategies. Convincing evidence suggests that peroxisome proliferator-activated receptor γ (PPARγ) activation is a stimulative factor against the hindered process of oligodendrocyte (OL) differentiation. However, much remains unknown about its promotive mechanism. Our previous study indicated that alpha-asaronol (α-asaronol) could alleviate myelination disorder in a neonatal PWMI rat model, but the mechanism remained unclear. In this study, we demonstrated that α-asaronol attenuated cognitive deficits, repaired myelin damage, and stimulated OL differentiation in the corpus callosum of PWMI rats. Co-immunoprecipitation analysis confirmed that α-asaronol induced the binding of PPARγ with its coactivator peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), which in turn activated oligodendroglial PPARγ. This activation subsequently upregulated the expression of phosphatase and tensin homolog (PTEN) and pro-differentiation-associated genes of Cnp1 and Klk6 and downregulated the expression of Clk1. However, the benefits of α-asaronol were blocked by GW9662, an antagonist of PPARγ. Moreover, α-asaronol also promoted OPC differentiation under oxygen-glucose deprivation conditions. In conclusion, α-asaronol can promote OL differentiation and myelination and alleviate cognitive deficits in neonatal PWMI rats by activating PPARγ and modulating OL differentiation-associated gene expression. This study suggests that α-asaronol may be a potential therapeutic drug for myelination failure in PWMI.

Abstract Background Plants suffer from various abiotic stresses during their lifetime, of which drought and salt stresses are two main factors limiting crop yield and quality. Previous studies have shown that abscisic acid (ABA) responsive element binding protein (AREB)/ ABRE binding factors (ABFs) in bZIP transcription factors are involved in plant stress response in an ABA-dependent manner. However, little is known about the properties and functions of AREB/ABFs, especially ABF3, in cotton. Results Here, we reported the cloning and characterization of GhABF3. Expression of GhABF3 was induced by drought,salt and ABA treatments. Silencing of GhABF3 sensitized cotton to drought and salt stress, which was manifested in decreased cellular antioxidant capacity and chlorophyll content. Overexpression of GhABF3 significantly improved the drought and salinity tolerance of Arabidopsis and cotton. Exogenous expression of GhABF3 resulted in longer root length and less leaf wilting under stress conditions in Arabidopsis thaliana. Overexpressing GhABF3 significantly improved salt tolerance of upland cotton by reducing the degree of cellular oxidation, and enhanced drought tolerance by decreasing leaf water loss rate. The increased expression of GhABF3 up-regulated the transcriptional abundance of downstream ABA-inducible genes under salt stress in Arabidopsis. Conclusion In conclusion, our results demonstrated that GhABF3 plays an important role in plant drought and salt tolerance. Manipulation of GhABF3 by biotechnology might be an important strategy to alter the stress resistance of cotton.

The HVA22 family of genes, induced by abscisic acid and stress, encodes a class of stress response proteins with a conserved TB2/DP1/HVA22 domain that are unique among eukaryotes. Previous studies have shown that HVA22s play an important role in plant responses to abiotic stresses. In the present study, 34, 32, 16, and 17 HVA22s were identified in G. barbadense, G. hirsutum, G. arboreum, and G. raimondii, respectively. These HVA22 genes were classified into nine subgroups, randomly distributed on the chromosomes. Synteny analysis showed that the amplification of the HVA22s were mainly due to segmental duplication or whole genome replication (WGD). Most HVA22s promoter sequences contain a large number of drought response elements (MYB), defense and stress response elements (TC-rich repeats), and hormone response elements (ABRE, ERE, SARE, etc.), suggesting that HVA22s may respond to adversity stresses. Expression profiling demonstrated that most GhHVA22s showed a constitutive expression pattern in G. hirsutum and could respond to abiotic stresses such as salt, drought, and low temperature. Overexpression of GhHVA22E1D (GH_D07G0564) in Arabidopsis thaliana enhances salt and drought tolerance in Arabidopsis. Virus-induced gene silencing of GhHVA22E1D reduced salt and drought tolerance in cotton. This indicates that GhHVA22E1D plays an active role in the plant response to salt stress and drought stress. GhHVA22E1D may act in plant response to adversity by altering the antioxidant capacity of plants. This study provides valuable information for the functional genomic study of the HVA22 gene family in cotton. It also provides a reference for further elucidation of the functional studies of HVA22 in plant resistance to abiotic stress response.

Abstract This study aimed to investigate the role of deubiquitinating enzyme 3 (DUB3) in the regulation of Krüppel-like factor 4 (KLF4) expression in hepatocellular carcinoma (HCC). Gain- and loss-of-function assay, luciferase reporter assay, co-immunoprecipitation, and intracellular and extracellular deubiquitination assays were conducted in vitro. A tumor xenograft mouse model was established. The expression of DUB3 and KLF4 was examined in HCC patient specimens. The results showed that DUB3 upregulated KLF4 expression by deubiquitinating and stabilizing KLF4 protein in HCC cells through binding with KLF4. DUB3 inhibited HCC cell proliferation in vitro and tumor growth in vivo while enhancing the chemosensitivity of HCC cells in a KLF4-dependent manner. Furthermore, KLF4 promoted DUB3 transcription by binding to the DUB3 promoter. In HCC patients, DUB3 expression positively correlated with KLF4 expression in HCC tissues. Low DUB3 expression predicted worse overall survival and recurrence in HCC patients. In conclusion, this study revealed a positive DUB3/KLF4 feedback loop that inhibits tumor growth and chemoresistance in HCC. These results suggest that DUB3/KLF4 activation might be a potential therapeutic approach for HCC treatment.

Background The endothelium is essential for maintaining vascular physiological homeostasis and the endothelial injury leads to the neointimal hyperplasia because of the excessive proliferation of vascular smooth muscle cells. Endothelial Foxp1 (forkhead box P1) has been shown to control endothelial cell (EC) proliferation and migration in vitro. However, whether EC‐Foxp1 participates in neointimal formation in vivo is not clear. Our study aimed to investigate the roles and mechanisms of EC‐Foxp1 in neointimal hyperplasia. Methods and Results The wire injury femoral artery neointimal hyperplasia model was performed in Foxp1 EC‐specific loss‐of‐function and gain‐of‐function mice. EC‐Foxp1 deletion mice displayed the increased neointimal formation through elevation of vascular smooth muscle cell proliferation and migration, and the reduction of EC proliferation hence reendothelialization after injury. In contrast, EC‐Foxp1 overexpression inhibited the neointimal formation. EC‐Foxp1 paracrine regulated vascular smooth muscle cell proliferation and migration via targeting matrix metalloproteinase‐9. Also, EC‐Foxp1 deletion impaired EC repair through reduction of EC proliferation via increasing cyclin dependent kinase inhibitor 1B expression. Delivery of cyclin dependent kinase inhibitor 1B‐siRNA to ECs using RGD (Arg‐Gly‐Asp)‐peptide magnetic nanoparticle normalized the EC‐Foxp1 deletion‐mediated impaired EC repair and attenuated the neointimal formation. EC‐Foxp1 regulates matrix metalloproteinase‐9/cyclin dependent kinase inhibitor 1B signaling pathway to control injury induced neointimal formation. Conclusions Our study reveals that targeting EC‐Foxp1‐matrix metalloproteinase‐9/cyclin dependent kinase inhibitor 1B pathway might provide future novel therapeutic interventions for restenosis.

To meet the comprehensive demand for flexible microwave absorbing (MA) materials, a novel MA rubber containing homemade Polypyrrole nanotube (PPyNT) is produced based on the natural rubber (NR) and acrylonitrile-butadiene rubber (NBR) blends. To achieve the optimal MA performance in the X band, the PPyNT content and NR/NBR blend ratio are adjusted in detail. The 6 phr PPyNT filled NR/NBR (90/10) composite has the superior MA performance with the minimum reflection loss value of −56.67 dB and the corresponding effective bandwidth of 3.7 GHz at a thickness of 2.9 mm, which has the merits in virtue of achieving strong absorption and wide effective absorption band with low filler content and thickness compared to most reported microwave absorbing rubber materials over the same frequency. This work provides new insight into the development of flexible microwave-absorbing materials.

Furosemide is a widely used loop diuretic in the treatment of congestive heart failure and edema. During the preparation of furosemide, a new process-related impurity G in the levels ranging from 0.08% to 0.13% was detected in pilot batches by a new high performance liquid chromatography (HPLC) method. The new impurity was isolated and characterized by comprehensive analysis of FT-IR, Q-TOF/LC-MS, 1D-NMR (1H, 13C, and DEPT), and 2D-NMR (1H-1H-COSY, HSQC, and HMBC) spectroscopy data. The possible formation pathway of impurity G was also discussed in detail. Moreover, a novel HPLC method was developed and validated for the determination of impurity G and the other six known impurities registered in the European Pharmacopoeia as per ICH guidelines. The HPLC method was validated with respect to system suitability, linearity, the limit of quantitation, the limit of detection, precision, accuracy, and robustness. The characterization of impurity G and the validation of its quantitative HPLC method were reported for the first time in this paper. Finally, the toxicological properties of impurity G were predicted by the in silico webserver ProTox-II.

M1 macrophages are an important cell type related to tumor immunology and are known to phagocytose cancer cells. In previous studies, the organogermanium compound poly-trans-[(2-carboxyethyl)germasesquioxane] (Ge-132) and its hydrolysate, 3-(trihydroxygermyl) propanoic acid (THGP), have been reported to exert antitumor effects by activating NK cells and macrophages through the induction of IFN-γ activity in vivo. However, the detailed molecular mechanism has not been clarified. In this study, we found that macrophages differentiate into the M1 phenotype via NF-κB activation under long-term culture in the presence of THGP in vitro and in vivo. Furthermore, long-term culture with THGP increases the ability of RAW 264.7 cells to suppress B16 4A5 melanoma cell proliferation. These mechanisms indicate that THGP promotes the M1 polarization of macrophages and suppresses the expression of signal-regulatory protein alpha (SIRP-α) in macrophages and CD47 in cancers. Based on these results, THGP may be considered a new regulatory reagent that suppresses tumor immunity.

Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) and excessive accumulation of dysfunctional PVAT are hallmarks of pathogenesis after angioplasty. Recent genome-wide association studies reveal that single-nucleotide polymorphism (SNP) in MIA3 is associated with atherosclerosis-relevant VSMC phenotypes. However, the role of MIA3 in the vascular remodeling response to injury remains unknown. Here, we found that expression of MIA3 is increased in proliferative VSMCs and knockdown of MIA3 reduces VSMCs proliferation, migration, and inflammation, whereas MIA3 overexpression promoted VSMC migration and proliferation. Moreover, knockdown of MIA3 ameliorates femoral artery wire injury-induced neointimal hyperplasia and increases brown-like perivascular adipocytes. Collectively, the data suggest that MIA3 deficiency prevents neointimal formation by decreasing VSMC proliferation, migration, and inflammation and maintaining BAT-like perivascular adipocytes in PVAT during injury-induced vascular remodeling, which provide a potential therapeutic target for preventing neointimal hyperplasia in proliferative vascular diseases.

Background and Aims: Coronary artery disease (CAD) is usually caused by atherosclerosis, which is associated with general obesity and stronger associations with localized ectopic fat depots have been reported. We measured body ectopic fat distribution in Chinese patients to determine the association with coronary artery atherosclerosis (CA). Methods: Patients undergoing coronary computed tomography angiography (CCTA) who agreed to participate in the study (n = 750, 50.4% men, mean age 64.8 years) had cardiovascular disease and risk assessment. Body ectopic fat depots were measured from CT and their association with CA, determined from CCTA, was evaluated by univariate and multivariate logistic regression models. Results: CAD with CA (CAD-CA) was present in 57.2% of participants with CAD of moderate/severe CA (CAD-msCA) present in 23.5% and both were significantly more frequent in men than in women. Overall, men had greater body mass index (BMI) but there was no difference in waist circumference (WC) between genders. However, significantly higher visceral adipose tissue (VAT) and periaortic fat volume (PAFV) were observed in men, whereas women had significantly higher abdominal subcutaneous adipose tissue (SAT). With increasing age, there was a significant decline in BMI, WC and SAT in men, but a significant increase of WC and VAT, PAFV and epicardial fat volume (EFV) in women. A high proportion of non-calcified plaques was observed in CAD-CA, 55.3% in CAD of minimal/mild CA (CAD-mmCA) with 38.7% exclusively non-calcified plaques, and 59.7% in CAD-msCA with multiple type plaques containing non-calcified ones. Multivariate logistic regression showed a significant association of PAFV with CAD-CA and CAD-msCA that was independent of general obesity and clinical risk factors, and independent of abdominal obesity in the highest PAFV quartile patients. VATA was associated with an increased prevalence of CAD-msCA in the patients in the upper 2 VATA quartiles that was independent of clinical risk factors and both general and abdominal obesity. Conclusions: We found age and gender differences of body ectopic fat distribution in Chinese patients with higher VAT and PAFV in men and higher SAT in women. With increased age, there was a decline of WC and SAT in men but not in women and an increase in WC, VAT and PAFV in women but not in men. PAFV was significantly associated with overall CAD-CA and CAD-msCA, while VAT was associated with CAD-msCA.

Heterogeneous catalytic ozonation is an alternative approach for the removal of refractory pollutants from water, and the fabrication of mesoporous materials with high dispersibility would enhance the catalytic efficiency. A mesoporous CeO2 was prepared by the nanocasting method with SBA-15 as a hard template, and was investigated in the catalytic ozonation of atrazine. The synthetical CeO2 nanorods have a specific surface area of 95.08 m2/g, a diameter of 10.16 nm, and a spacing of 2.18 nm. The removal rate of atrazine was 85.5%, 64.8%, and 46.4% in the order of catalytic ozonation by synthetical CeO2 > single ozonation > catalytic ozonation by commercial CeO2, respectively. The superior activity of the synthetical CeO2 could be attributed to the well-ordered mesoporous structure, the high surface area, and the redox Ce3+/Ce4+ cycling. Moreover, eight organic intermediates were identified after one minute of catalytic ozonation of atrazine, and the cleavage of the ethylamino group was proposed as the main pathway of atrazine degradation.

PDCD10, also known as CCM3, is a gene found to be associated with the human disease cerebral cavernous malformations (CCMs). PDCD10 forms a complex with GCKIII kinases including STK24, STK25, and MST4. Studies in C. elegans and Drosophila have shown a pivotal role of the PDCD10-GCKIII complex in maintaining epithelial integrity. Here, we found that mice deficient of Pdcd10 or Stk24/25 in the kidney tubules developed polyuria and displayed increased water consumption. Although the expression levels of aquaporin genes were not decreased, the levels of total and phosphorylated aquaporin 2 (Aqp2) protein in the apical membrane of tubular epithelial cells were decreased in Pdcd10- and Stk24/25-deficient mice. This loss of Aqp2 was associated with increased expression and membrane targeting of Ezrin and phosphorylated Ezrin, Radixin, Moesin (p-ERM) proteins and impaired intracellular vesicle trafficking. Treatment with Erlotinib, a tyrosine kinase inhibitor promoting exocytosis and inhibiting endocytosis, normalized the expression level and membrane abundance of Aqp2 protein, and partially rescued the water reabsorption defect observed in the Pdcd10-deficient mice. Our current study identified the PDCD10-STK-ERM signaling pathway as a potentially novel pathway required for water balance control by regulating vesicle trafficking and protein abundance of AQP2 in the kidneys.

Oxidative stress in adipose tissue is a crucial pathogenic mechanism of obesity-associated cardiovascular diseases. Chronic low-grade inflammation caused by obesity increases ROS production and dysregulation of adipocytokines. Leonurine (LEO) is an active alkaloid extracted from Herba Leonuri and plays a protective role in the cardiovascular system. The present study tested whether LEO alleviates inflammation and oxidative stress, and improves vascular function in an obese mouse model. Here, we found that obesity leads to inflammation and oxidative stress in epididymal white adipose tissue (EWAT), as well as vascular dysfunction. LEO significantly improved inflammation and oxidative stress both in vivo and in vitro. Obesity-induced vascular dysfunction was also improved by LEO as evidenced by the ameliorated vascular tone and decreased mesenteric artery fibrosis. Using mass spectrometry, we identified YTHDF1 as the direct target of LEO. Taken together, we demonstrated that LEO improves oxidative stress and vascular remodeling induced by obesity and targets YTHDF1, raising the possibility of LEO treating other obesity-related metabolic syndromes.

Neuropathic pain is often closely associated with nerve injury or inflammation, and the role of traditional nonsteroidal anti-inflammatory drugs as adjuvants for treating chemotherapy-induced peripheral neuropathic pain remains unclear. In this study, the potential synergistic antinociceptive effects of indomethacin–pregabalin and meloxicam–pregabalin were evaluated in paclitaxel-induced neuropathic pain and carrageenan-induced inflammatory pain in rodents. Although indomethacin and meloxicam alone only slightly relieved mechanical allodynia in the above two models, isobolographic analysis showed that the combination of indomethacin or meloxicam with pregabalin produced significant synergistic antinociceptive effects for paclitaxel-induced neuropathic pain (IN-PGB, experimental ED25 = [4.41 (3.13–5.82)] mg/kg, theoretical ED25 = [8.50 (6.62–10.32)] mg/kg; MEL-PGB, experimental ED25 = [3.96 (2.62–5.46)] mg/kg, theoretical ED25 = [7.52 (5.73–9.39)] mg/kg). In addition, MEL-PGB dosed via intraplantar injection into the left paw, intragastric injection, or intraperitoneal injection reversed paclitaxel-induced allodynia, indicating that they may act at multiple sites in the neuroaxis and periphery. However, indomethacin–pregabalin and meloxicam–pregabalin exerted antagonistic antiallodynic interactions in carrageenan-induced inflammatory pain in rats. Taken together, coadministration of indomethacin or meloxicam with pregabalin may possess potential therapeutic advantages for treating chemotherapy-induced neuropathic pain.

Olanzapine is a commonly used drug in the treatment of schizophrenia, but its clinical application has been restricted by metabolic-related side effects. In order to mitigate the weight gain side effects caused by olanzapine, other drugs with different targets were selected for combined use and evaluated in animal models of schizophrenia. SEP-363856 is a novel psychotropic agent which is under phase III clinical trials for schizophrenia treatment. The aim of the research was to evaluate whether co-administration of olanzapine and SEP-363856 exerts synergistic anti-schizophrenic effects in the apomorphine (APO)-induced climbing test, the MK-801-induced hyperactivity test, and the Morris water maze test, and therefore reduces the weight gain side effects induced by olanzapine. Through isobolographic analysis, the results showed a synergistic interaction in the climbing test; the experimental ED30 (3 mg/kg) was significantly smaller (p < 0.05) than the theoretical ED30 (5 mg/kg). Additionally, such potentiating effects appeared additive in the MK-801 challenge experiment. Co-treatment with an effective dose of olanzapine and a low dose of SEP-363856 reversed MK-801-induced cognitive impairment symptoms in mice. Moreover, combination treatment with olanzapine and SEP-363856 controls sustained weight gain in mice with chronic exposure to olanzapine. These results support further clinical trials to test the effectiveness of co-treatment of olanzapine and SEP-363856 for controlling symptoms and weight gain in patients with schizophrenia during antipsychotic treatments.

Abstract Background Angiogenesis is defined as a new blood vessel sprouting from pre-existing vessels, and the sprouting angiogenesis is the start phase of angiogenesis, which is critical for both physiological and pathological processes, such as embryonic development, organ growth, wound healing, tumor growth, diabetic retinopathy and age-related macular degeneration. Better understanding of the mechanisms of sprout angiogenesis will provide a rationale for the treatments of these angiogenesis related diseases. Methods mT/mG tool mice are crossed with Apln-CreERT mice to generate Apln-CreERT: mT/mG mice, then we used neonatal retinal angiogenesis model to observe the angiogenic pattern of Apln-CreERT:mT/mG mice compared with Cdh5-CreERT:mT/mG mice. FACS analysis was used to sort eGFP and tdTomato endothelial cells (ECs) for measuring Apelin and Cdh5 expression. Retinal sprouting angiogenesis pattern was also observed at different neonatal time when induced by tamoxifen and at hypoxia condition, as well as in vivo tumor in real-time angiogenesis in a dorsal skinfold window chamber in Apln-CreERT:mT/mG mice. Results Apln-CreERT:mT/mG mice exhibited eGFP signal only in the sprouting angiogenesis, with less eGFP expression in the retinal “optic nerve” area than in that of Cdh5-CreERT: mT/mG mice, which might be due to relative mature vessels in the “optic nerve” area. The ECs sorted by FACS confirmed that the Apelin expression level was higher in eGFP ECs than tdTomato ECs of “optic nerve” area. Further we found that GFP-labeled sprouting angiogenesis decreased gradually following tamoxifen administration from P5-P7, but increased significantly during hypoxia in Apln-CreERT:mT/mG mice. At last, using Apln-CreERT:mT/mG mice we found tumor sprouting angiogenesis in dorsal skinfold, but not in the normal skinfold tissue. Conclusions Apln-CreERT:mT/mG mouse line is a useful tool to differentiate sprouting angiogenesis from whole blood vessels in the investigation of retinal and tumor sprouting angiogenesis in vivo.

The valence transition of 4f electron states in rare-earth compounds is accompanied by a discontinuous change in the Kondo temperature, an energy scale tied to the interaction of the 4f states with the conduction-band states (c-f hybridization). The c-f hybridization causes the formation of heavy quasiparticle bands and produces a hybridization gap. Whether the hybridization gap develops at the valence-transition temperature T_{V} is one of the key questions in the 4f-electron systems. In our angle-resolved photoemission spectroscopy performed using synchrotron radiation, we observed such a hybridization gap of the valence-transition compound YbInCu_{4}. We found that the gap increases below T_{V} and has a momentum dependence. Notably, the gap enhancement occurs along with a substantial energy shift of the conduction bands. We suggest that the c-f hybridization and the enhancement of the density of states at E_{F} should be incorporated in the scenarios of the valence transition in YbInCu_{4}.

Abstract Background In 2004, the media repeatedly reported water pollution and "cancer villages" along the Huai River in China. Due to the lack of death records for more than 30 years, a retrospective survey of causes of death using verbal autopsy was carried out to investigate cancer rates in this area. Methods An epidemiologic study was designed to compare numbers of deaths and causes of death between the study areas with water pollution and the control areas without water pollution in S County and Y District in 2005. The study areas were selected based on the distribution of the Huai River and its tributaries. Verbal autopsy was used to assist cause of death (COD) diagnoses and to verify mortality rates. The standard mortality rates (SMRs) of cancer in the study area were compared with those in the control areas. In order to verify the difference between mortality rates due to cancers in the study and the control areas, patients who reported having cancer in the survey received a second diagnosis by national and provincial oncologists with pathological and laboratory examinations. Comparisons were made to determine if differential cancer prevalence rates in the study and control areas were similar to the difference in mortality due to cancer in these study and control areas. Mortality rates of cancers in study and control areas were also compared with national statistics for the rural population of China. Results Over five years, 3,301 deaths were identified, including 1,158 cancer deaths. The annual average SMRs of cancer in the study areas of S County and Y District were 277.8/100,000 and 223.6/100,000, respectively, which is three to four times higher than those in the control areas. In addition, a total of 626 cases of cancer in the study and control areas were confirmed. The prevalence rates of cancer were 545/100,000 and 128.1/100,000 per year in the study and control areas in S County, respectively, and 440.9/100,000 and 200/100,000 per year in the study and control areas in Y District, respectively. The mortality and prevalence rates of digestive cancers were higher in the study areas than the control areas. In 2000, the SMR for cancer in rural areas nationwide was 120.9/100,000, and in study areas in S County and Y District, the excess rates of deaths were 184/100,000 and 138.8/100,000, respectively. Conclusions The death rates of digestive cancers were much higher in the study areas of S County and Y District. The patterns for between-area differences in prevalence and mortality rates of cancer were similar. Verbal autopsy is shown to be a useful tool in retrospective mortality surveys in low-resource areas with limited access to health care.