Search

In order to set up a reliable prediction system for the tumor grade and prognosis in glioma patients, we clarify the complicated crosstalk of Annexin A2 (ANXA2) with Glypican 1 (GPC1) and demonstrate whether combined indexes of ANXA2 and GPC1 could improve the prognostic evaluation for glioma patients. We found that ANXA2-induced glioma cell proliferation in a c-Myc-dependent manner. ANXA2 increased the expression of GPC1 via c-Myc and the upregulated GPC1 further promoted the c-Myc level, forming a positive feedback loop, which eventually led to enhanced proliferation of glioma cells. Both mRNA and protein levels of ANXA2 were upregulated in glioma tissues and coincided with the overexpression of GPC1. Besides, we utilized tissue microarrays (TMAs) and immunohistochemistry to demonstrate that glioma patients with both high expression of ANXA2 and GPC1 tended to have higher rate of tumor recurrence and shorter overall survival (OS). In conclusion, the overexpression of ANXA2 promotes proliferation of glioma cells by forming a GPC1/c-Myc positive feedback loop, and ANXA2 together with its downstream target GPC1 could be a potential “combination biomarker” for predicting prognosis of glioma patients.

Background Programmed cell death protein 1 (PD-1) blockade is a major advance in the treatment of malignancies, but there remain many problems in efficacy evaluation. The aim of this study was to determine whether dynamic monitoring of serum specific tumor markers (SSTMs) could predict the response to PD-1 blockade and prognosis in patients with malignancies. Methods The dynamic changes in SSTMs in 27 patients between January 1, 2018 and July 31, 2019 were analyzed retrospectively. The association between the SSTM response and the radiological response was evaluated using the χ2 test and Spearman’s correlation analysis. Kaplan-Meier estimates and the log rank test were used to explore the correlation of SSTM dynamics with progression-free survival (PFS) and overall survival (OS). Results In this study, 85.3% of patients with malignant tumors had detectable SSTM. According to the changes of SSTM within the first 12 weeks of treatment, the patients were divided into a tumor marker increased group and a tumor marker decreased group. The change in SSTM was strongly associated with the change in target lesions (χ2=15.326, P≤0.001), and there was a positive correlation between them (Pearson Correlation r=0.727, P

Hypertensive cardiac remodeling is a constellation of abnormalities that includes cardiomyocyte hypertrophy and death and tissue fibrosis. Adenosine is a long-known vasodilator, through interacting with its four cell surface receptor subtypes in cardiovascular system. However, it is unclear that whether adenosine A2A receptor (A2AR) activation is involved in the cardiac remodeling in hypertension. WT mice were utilized to induce DOCA-salt sensitive hypertension and received A2AR agonist CGS21680 or antagonist KW6002 treatment. Cardiac functional phenotyping measurement by echocardiography showed that CGS21680 improved cardiac dysfunction in DOCA-salt mice. Moreover, CGS21680 reduced cardiomyocyte hypertrophy, cardiac inflammation and fibrosis. However, iBAT depletion surgery induces dramatic cardiac remodeling in DOCA-salt mice, and the protective function of CGS21680 was blocked without intact iBAT. Mechanistically, A2AR agonist CGS21680 increased iBAT-derived fibroblast growth factor 21 (FGF21). Our data suggest that activation of A2AR could be a potential therapeutic strategy in preventing heart damage in hypertension.

Transmissible gastroenteritis coronavirus (TGEV) is enteropathogenic coronavirus that causes diarrhea in pigs, and is associated with high morbidity and mortality in sucking piglets. The TGEV membrane (M) protein is a decisive protein for the proliferation of viral proteins, and is associated with virus assembly and budding. To identify the cellular proteins that interact with the TGEV M protein, yeast two-hybrid screening was employed, and seven cellular proteins were identified M-binding partners. Using the GST pull-down approach and a CO-IP assay, the M protein was found to interact with porcine intestinal cells via eukaryotic translation initiation factor 4-alpha (EIF4A2), an essential component of the cellular translational machinery. Additionally, confocal microscopy revealed that EIF4A2 and M were colocalized in the cytoplasm. Furthermore, the function of EIF4A2 in intestinal cells during TGEV infection was examined. A knockdown of EIF4A2 by siRNA markedly decreased M protein proliferation and TGEV replication in target cells. Thus demonstrating that EIF4A2 plays a significant role in TGEV replication. The present study provides mechanistic insight into the interaction between the TGEV M protein and intestinal cells which contributes to the understanding of coronavirus replication and may be useful for the development of novel therapeutic strategies for TGEV infection., Highlights • Yeast two-hybrid system identified seven proteins to interact with TGEV M protein. • EIF4A2 was confirmed to interact with and TGEV M protein via GST-pull down and CO-IP. • Immunofluorescence revealed colocalization of EIF4A2 and M protein in the cytoplasm. • EIF4A2 siRNA knockdown reduced TGEV replication in porcine IECs. • EIF4A2 may be associated with TGEV replication in porcine intestinal cells.

Obesity-induced secretory disorder of adipose tissue–derived factors is important for cardiac damage. However, whether platelet-derived growth factor-D (PDGF-D), a newly identified adipokine, regulates cardiac remodeling in angiotensin II (AngII)–infused obese mice is unclear. Here, we found obesity induced PDGF-D expression in adipose tissue as well as more severe cardiac remodeling compared with control lean mice after AngII infusion. Adipocyte-specific PDGF-D knockout attenuated hypertensive cardiac remodeling in obese mice. Consistently, adipocyte-specific PDGF-D overexpression transgenic mice (PA-Tg) showed exacerbated cardiac remodeling after AngII infusion without high-fat diet treatment. Mechanistic studies indicated that AngII-stimulated macrophages produce urokinase plasminogen activator (uPA) that activates PDGF-D by splicing full-length PDGF-D into the active PDGF-DD. Moreover, bone marrow–specific uPA knockdown decreased active PDGF-DD levels in the heart and improved cardiac remodeling in HFD hypertensive mice. Together, our data provide for the first time a new interaction pattern between macrophage and adipocyte: that macrophage-derived uPA activates adipocyte-secreted PDGF-D, which finally accelerates AngII-induced cardiac remodeling in obese mice.

Transmissible gastroenteritis (TGE) and porcine epidemic diarrhea (PED) are highly transmissible intestinal infections caused by transmissible gastroenteritis virus (TGEV) and porcine epidemic diarrhea virus (PEDV), respectively. They are clinically associated with vomiting, diarrhea, and dehydration in piglets. An imbalance in Na+ uptake by intestinal epithelial cells causes TGEV/PEDV-induced diarrhea. However, the mechanism by which TGEV/PEDV-infection in piglets causes Na+ imbalance diarrhea has not been elucidated. In the present study, we demonstrated that specific inhibition of NHE3 activity caused small intestinal bulging, intestinal wall thinning and severe diarrhea in piglets, consistent with the signs of TGEV/PEDV infection. This study further elucidated the role of NHE3 in TGEV/PEDV-induced diarrhea. In this study, small intestinal epithelial cells (IPEC-J2) were used as a model of infection. The results showed that TGEV/PEDV infection reduced NHE3 activity and Na+ uptake in IPEC-J2 cells. Further studies revealed that the use of NHE3-specific inhibitors could reduce the amount of cell membrane NHE3, thereby decreasing Na+ uptake and ultimately leading to diarrhea. Transcriptomic studies performed on obtained jejunal tissues were also consistent with pre-laboratory results. This study will provide a basis for understanding Na+ imbalance diarrhea caused by TGEV/PEDV, as well as for elucidating the diarrheal pathogenesis of other members of α-animal coronaviruses.

Colorectal cancer has one of the highest mortality rates among malignant tumors, and most patients with non-microsatellite instability-high (MSI-H) colorectal cancer do not benefit from targeted therapy or immune checkpoint inhibitors. Identification of immunogenic neoantigens is a promising strategy for inducing specific antitumor T cells for cancer immunotherapy. Here, we screened potential high-frequency neoepitopes from non-MSI-H colorectal cancer and tested their abilities to induce tumor-specific cytotoxic T cell responses. Three HLA-A2-restricted neoepitopes (P31, P50, and P52) were immunogenic and could induce cytotoxic T lymphocytes in peripheral blood mononuclear cells from healthy donors and colorectal cancer patients. Cytotoxic T lymphocytes induced in HLA-A2.1/Kb transgenic mice could recognize and lyse mutant neoepitope-transfected HLA-A2+ cancer cells. Adoptive transfer of cytotoxic T lymphocytes induced by the peptide pool of these three neoepitopes effectively inhibited tumor growth and increased the therapeutic effects of anti-PD-1 antibody. These results revealed the potential of high-frequency mutation-specific peptide-based immunotherapy as a personalized treatment approach for patients with non-MSI-H colorectal cancer. The combination of adoptive T cell therapy based on these neoepitopes with immune checkpoint inhibitors, such as anti-PD-1, could provide a promising treatment strategy for non-MSI-H colorectal cancer.

Porcine epidemic diarrhea virus (PEDV) is an enteropathogenic coronavirus; it causes diarrhea in pigs and is associated with high morbidity and mortality in sucking piglets. In this study, we performed in vitro and in vivo experiments to determine the inhibitory effects of Lactobacillus plantarum metabolites (LPM) on PEDV replication. Gas chromatography–mass spectrometry revealed exopolysaccharides to be one of the main components of LPM. We then determine whether L. plantarum exopolysaccharides (LPE) have an antiviral effect and also detected the expression levels of the apoptosis-related genes Bax and Bcl-2 and of the pro-apoptotic protein caspase-3. Further, we assessed the transcription levels of an immune-related protein (STAT1) and antiviral factors (MX1, MX2, ISG15, ZAP, PKR, and OAS1). Our results showed that the most effective method was to pretreat cells with LPM and that the optimal dose of LPM that could be safely administered to Vero cells was 1/8 times of the stock solution. LPE had a strong inhibitory effect on PEDV; the most effective method of administration was to co-incubate cells with LPE and PEDV, and the optimal concentration of LPE was 1.35 mg/mL. To conclude, LPE prevented PEDV adsorption and also alleviated inflammatory responses and induced early apoptosis of injured cells, but it could not regulate the immune function of cells.

Highlights • Decreased of apical of NHE3 protein expression and Na+/H+ exchange activity after TGEV infected IPEC-J2. • SGLT1 can regulation the trafficking of NHE3 by p38MAPK/AKt2 singal pathway and show a corporate relationship. • TGEV infection causes an increase in the expression of total SGLT1 protein. • TGEV infection attenuates the translocation and exchange activity of NHE3 via the p38MAPK/AKt2 signaling pathway., Transmissible gastroenteritis virus (TGEV) primarily replicates in intestinal epithelial cells and causes severe damage to host cells, resulting in diarrhea. Surface NHE3 serves as the key regulatory site controlling electroneutral Na+ absorption. In this study, our results showed that the surface NHE3 content was significantly reduced following TGEV infection, whereas the total level of protein expression was not significantly changed, and NHE3 activity gradually decreased with prolonged infection time. We then inhibited SGLT1 expression by lentiviral interference and drug inhibition, respectively. Inhibition studies showed that the level of phosphorylation of the downstream key proteins, MAPKAPK-2 and EZRIN, in the SGLT1-mediated p38MAPK/AKt2 signaling pathway was significantly increased. The surface NHE3 expression was also significantly increased, and NHE3 activity was also significantly enhanced. These results demonstrate that a TGEV infection can inhibit NHE3 translocation and attenuates sodium-hydrogen exchange activity via the SGLT1-mediated p38MAPK/AKt2 signaling pathway, affecting cellular electrolyte absorption leading to diarrhea.

Obesity increases the risk of vascular diseases, including aortic aneurysm (AA). Perivascular adipose tissue (PVAT) surrounding arteries are altered during obesity. However, the underlying mechanism of adipose tissue, especially PVAT, in the pathogenesis of AA is still unclear. Here we showed that angiotensin II (AngII) infusion increases the incidence of AA in leptin-deficient obese mice (ob/ob) and high-fat diet–induced obese mice with adventitial inflammation. Furthermore, transcriptome analysis revealed that platelet-derived growth factor-D (PDGF-D) was highly expressed in the PVAT of ob/ob mice. Therefore, we hypothesized that PDGF-D mediates adventitial inflammation, which provides a direct link between PVAT dysfunction and AA formation in AngII-infused obese mice. We found that PDGF-D promotes the proliferation, migration, and inflammatory factors expression in cultured adventitial fibroblasts. In addition, the inhibition of PDGF-D function significantly reduced the incidence of AA in AngII-infused obese mice. More importantly, adipocyte-specific PDGF-D transgenic mice are more susceptible to AA formation after AngII infusion accompanied by exaggerated adventitial inflammatory and fibrotic responses. Collectively, our findings reveal a notable role of PDGF-D in the AA formation during obesity, and modulation of this cytokine might be an exploitable treatment strategy for the condition.

The abnormally hyperphosphorylated tau is thought to be implicated in diabetes-associated cognitive deficits. The role of mammalian target of rapamycin (mTOR) / S6 kinase (S6K) signalling in the formation of tau hyperphosphorylation has been previously studied. Caveolin-1 (Cav-1), the essential structure protein of caveolae, promotes neuronal survival and growth, and inhibits glucose metabolism. In this study, we aimed to investigate the role of Cav-1 in the formation of tau hyperphosphorylation under chronic hyperglycemic condition (HGC). Diabetic rats were induced by streptozotocin (STZ). Primary hippocampal neurons with or without molecular intervention such as the transient over-expression or knock-down were subjected to HGC. The obtained experimental samples were analyzed by real time quantitative RT-PCR, Western blot, immunofluorescence or immunohistochemisty. We found: 1) that a chronic HGC directly decreases Cav-1 expression, increases tau phosphorylation and activates mTOR/S6K signalling in the brain neurons of diabetic rats, 2) that overexpression of Cav-1 attenuates tau hyperphosphorylation induced by chronic HGC in primary hippocampal neurons, whereas down-regulation of Cav-1 using Cav-1 siRNA dramatically worsens tau hyperphosphorylation via mTOR/S6K signalling pathway, and 3) that the down-regulation of Cav-1 induced by HGC is independent of mTOR signalling. Our results suggest that tau hyperphosphorylation and the sustained over-activated mTOR signalling under hyperglycemia may be due to the suppression of Cav-1. Therefore, Cav-1 is a potential therapeutic target for diabetes-induced cognitive dysfunction.

To investigate the osteoinductive mechanism triggered by hydroxyapatite/&beta, tricalcium phosphate (HA/&beta, TCP) biomaterials in mice which keep exercising. Methods: The HA/&beta, TCP biomaterials were implanted in the muscle of bilateral thighs (non-osseous sites) of eighty Balb/C mice. All animals were then randomly divided into 4 groups (n = 20). In group 1 (negative control group), the mice were fed routinely. In group 2 (running group), all mice were put on a treadmill which was set to a 60-degree incline. The mice ran 20 min thrice each day. A 5-minute break was included in the routine from day three onwards. In group 3 (weight-bearing group), all mice underwent weight-bearing running. The mice in this group performed the same routine as group 2 while carrying 5 g rubber weights. In group 4 (positive control group), dexamethasone was injected in the implanted sites of the biomaterials from the day of the operation. All mice were injected once per week and received a total of 8 injections. One and eight weeks after surgery, the blood serum was collected to detect inflammatory and immunological factors by ELISA. In addition to this, biomaterial specimens were obtained to observe inflammatory and osteogenic levels via histological staining and to facilitate analysis of the osteogenic mechanism by Western Blot. Results: The inflammation indexes caused by surgery were alleviated through running or weight-bearing running: The tumor necrosis factor-&alpha, (TNF-&alpha, ) and interleukin-6 (IL-6) levels were significantly reduced in groups 2 and 3 at week 8. Exercise also enhanced the secretion of interferon-&gamma, (IFN-&gamma, ) in mice, this can strengthen their immunity. The new bone tissues were observed in all groups, however, the area percentage of new bone tissues and the number of osteoblasts were highest in the weight-bearing group. Furthermore, the key proteins of wingless/integrated (Wnt) signaling pathway, Wnt1, Wnt3a, and &beta, catenin, were up-regulated during osteoinduction. This up-regulation activated runt-related transcription factor-2 (Runx2), increased the expression of osteopontin (OPN) and osteocalcin (OCN). Conclusion: Weight-bearing exercise can promote the bone and bone marrow formation through the Wnt signaling pathway: Observations documented here suggest that the proper exercise is beneficial to the recovery of bone damage.

Transmissible gastroenteritis (TGE), caused by transmissible gastroenteritis virus (TGEV), is one many gastrointestinal inflections in piglets, characterized by diarrhea, and high mortality. Probiotics are ubiquitous bacteria in animal intestines, which have many functions, such as promoting intestinal peristalsis and maintaining the intestinal balance. We found that the supernatant of the Lp-1 strain of Lactobacillus plantarum, isolated in our laboratory, and named Lp-1s had marked anti-TGEV effect on IPEC-J2 cells. Lp-1s could induce large amounts of interferon-β in IPEC-J2 cells in the early stage (6 h) of infection with TGEV, and increased the level of phosphorylated signal transducer and activator of transcription and its nuclear translocation in the late stage (24–48 h) of infection. This resulted in upregulated expression of interferon-stimulated genes, and increased the transcription and protein expression of antiviral proteins, resulting in an anti-TGEV effect.

Aims Aging is a risk factor for cardiovascular diseases and adaptive immunity has been implicated in angiotensin (Ang) II-induced target organ dysfunction. Herein, we sought to determine the role of T-cell senescence in Ang II-induced target organ impairment and to explore the underlying mechanisms. Methods and results Flow cytometric analysis revealed that T cell derived from aged mice exhibited immunosenescence. Adoptive transfer of aged T cells to immunodeficient RAG1 KO mice accelerates Ang II-induced cardiovascular and renal fibrosis compared with young T-cell transfer. Aged T cells also promote inflammatory factor expression and superoxide production in these target organs. In vivo and in vitro studies revealed that Ang II promotes interferon-gamma (IFN-γ) production in the aged T cells comparing to young T cells. Importantly, transfer of senescent T cell that IFN-γ KO mitigates the impairment. Aged T-cell-conditioned medium stimulates inflammatory factor expression and oxidative stress in Ang II-treated renal epithelial cells compared with young T cells, and these effects of aged T-cell-conditioned medium are blunted after IFN-γ-neutralizing antibody pre-treatment. Conclusion These results provide a significant insight into the contribution of senescent T cells to Ang II-induced cardiovascular dysfunction and provide an attractive possibility that targeting T cell specifically might be a potential strategy to treat elderly hypertensive patients with end-organ dysfunction.

Aging is an independent risk factor for vascular diseases. Perivascular adipose tissue (PVAT), an active component of the vasculature, contributes to vascular dysfunction during aging. Identification of underlying cell types and their changes during aging may provide meaningful insights regarding the clinical relevance of aging‐related vascular diseases. Here, we take advantage of single‐cell RNA sequence to characterize the resident stromal cells in the PVAT (PVASCs) and identified different clusters between young and aged PVASCs. Bioinformatics analysis revealed decreased endothelial and brown adipogenic differentiation capacities of PVASCs during aging, which contributed to neointimal hyperplasia after perivascular delivery to ligated carotid arteries. Mechanistically, in vitro and in vivo studies both suggested that aging‐induced loss of peroxisome proliferator‐activated receptor‐γ coactivator‐1 α (PGC1α) was a key regulator of decreased brown adipogenic differentiation in senescent PVASCs. We further demonstrated the existence of human PVASCs (hPVASCs) and overexpression of PGC1α improved hPVASC delivery‐induced vascular remodeling. Our finding emphasizes that differentiation capacities of PVASCs alter during aging and loss of PGC1α in aged PVASCs contributes to vascular remodeling via decreased brown adipogenic differentiation.

Beta3 adrenergic receptor (ADRB3) mediates vessel relaxation in the endothelium while it modulates lipolysis in the adipose tissue. However, the function and regulation mechanism of ADRB3 in the perivascular adipose tissue (PVAT), especially in hypertension, is still unclear. We show that ADRB3 protein is upregulated in the PVAT of deoxycorticosterone acetate-salt (DOCA-salt) hypertensive mice, with the characteristics of PVAT browning and increased uncoupling protein 1 (UCP1) expression. Inhibition of ADRB3 with selective antagonist SR59230A caused serious vascular injury in vivo, even though UCP1 expression was downregulated. ADRB3 protein was regulated by let-7b, which was decreased in the PVAT of the DOCA-salt group. These data reveal that ADRB3 in PVAT contributes to vascular function in the progression of hypertension.

To investigate the diagnostic value of multimodal ultrasound imaging composed of conventional ultrasonography (US), contrast-enhanced ultrasonography (CEUS), and shear wave elastography (SWE) for liver tumors. Between October 2017 and October 2019, US, CEUS, and SWE examinations of a total of 158 liver tumors in 136 patients at The First Affiliated Hospital of Nanchang University were performed. The histopathological or imaging diagnostic results were used as controls to evaluate the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of US, CEUS, SWE, and multimodal ultrasound imaging, which combines these 3 modes, in the differential diagnosis of benign and malignant liver tumors. Among the 158 tumors, there were 64 benign tumors, including 55 cases of hepatic hemangioma, 3 cases of focal nodular hyperplasia of the liver, 4 cases of hepatic cyst, and 2 cases of focal nonuniform distribution of fat in the liver. There were 94 malignant tumors, including 32 cases of hepatocellular carcinoma, 22 cases of intrahepatic cholangiocellular carcinoma, 29 cases of metastatic liver cancer, and 11 cases of dysplastic nodules in cirrhotic liver. In the diagnosis of benign and malignant liver tumors, the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were 82.56%, 68.06%, 75.96%, 75.53%, and 76.56% for US; 92.39%, 86.36%, 89.87%, 90.43%, and 89.06% for CEUS; 87.14%, 76.81%, 82.91%, 82.98%, and 82.81% for SWE; and 97.85%, 95.38%, 96.83%, 96.81%, and 96.88% for multimodal ultrasound imaging, respectively. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were all significantly higher for multimodal ultrasound imaging than those values for US, CEUS, and SWE (all P

Reduced glutathione (GSH) and some food-derived phenolic acids are welcome as natural antioxidants, but their synergistic antioxidant effect is unknown. The purpose of this study was to screen out the combination of GSH and the phenolic acid with synergistic antioxidant effect, improve their coexistence and protect the activity. Antioxidant evaluation systems including ABTS, DPPH, ORAC and reducing power assays were implemented, and dynamic light scattering and transmission electron microscopy analysis were carried out. Caffeic acid (CA) and GSH exhibited significant synergistic effect via electron transfer when the concentration ratio was 1:5. This combination was well embedded into chitosan-coated liposomes, which consist of evenly distributed and uniformly spherical microparticles, and its average particle size was 247.63 nm with polymer dispersity index of 0.29 and zeta potential of 57.73 mV. The encapsulation efficiencies of GSH and CA were 61.32% and 68.92%, respectively. The successfully prepared microparticles showed higher markedly antioxidant activity than the simple mixture and liposomes in 10-week storage. Therefore, co-encapsulation of GSH and CA using chitosan-coated liposomes is a potential approach to prepare natural potent antioxidant in food manufacture.

Transmissible gastroenteritis (TGE) has caused devastating economic losses to the swine industry worldwide, despite extensive research focusing on the pathogenesis of virus infection. The molecular pathogenic mechanism of TGEV-induced diarrhea in piglets is unknown. Intestinal diarrhea is closely related to the function of the Na+/H+ exchanger protein NHE3 in the brush border membrane of small intestine epithelial cells. The epidermal growth factor receptor (EGFR) may act to regulate NHE3 expression. In addition, EGFR may promote viral invasion of host cells. The present study aimed to determine whether NHE3 activity is regulated by altering EGFR expression to affect Na+ absorption in TGEV-infected intestinal epithelial cells. Porcine intestinal epithelial cells were used as models for TGEV infection. The results showed that Na+ absorption and NHE3 expression levels decreased in TGEV-infected cells. Proliferation of TGEV within IPEC-J2 cells could be inhibited by treatment with the EGFR inhibitor AG1478 and knockdown; resulting in recovery of Na+ absorption in TGEV infected cells and increasing the activity and expression of NHE3. Moreover, we demonstrated that NHE3 activity was regulated through the EGFR/ERK pathway. Importantly, NHE3 mobility on the plasma membrane of TGEV infected cells was significantly weaker than that in normal cells, and EGFR inhibition and knockdown recovered this mobility. Our research indicated that NHE3 activity was negatively regulated by EGFR in TGEV-infected intestinal epithelial cells.

The accumulation of palmitic acid (PA), implicated in obesity, can induce apoptotic cell death and inflammation of astrocytes. Caveolin-1 (Cav-1), an essential protein for astrocytes survival, can be degraded by autophagy, which is a double-edge sword that can either promote cell survival or cell death. The aim of this study was to delineate whether the autophagic degradation of Cav-1 is involved in PA-induced apoptosis and inflammation in hippocampal astrocytes. In this study we found that: (1) PA caused apoptotic death and inflammation by autophagic induction; (2) Cav-1 was degraded by PA-induced autophagy and PA induced autophagy in a Cav-1-independent manner; (3) the degradation of Cav-1 was responsible for PA-induced autophagy-dependent apoptotic cell death and inflammation; (4) chronic high-fat diet (HFD) induced Cav-1 degradation, apoptosis, autophagy, and inflammation in the hippocampal astrocytes of rats. Our results suggest that the autophagic degradation of Cav-1 contributes to PA-induced apoptosis and inflammation of astrocytes. Therefore, Cav-1 may be a potential therapeutic target for central nervous system injuries caused by PA accumulation.

Functional perivascular adipose tissue (PVAT) is necessary to maintain vascular physiology through both mechanical support and endocrine or paracrine ways. PVAT shows a brown adipose tissue (BAT)-like feature and the browning level of PVAT is dependent on the anatomic location and species. However, it is not clear whether PVAT browning is involved in the vascular tone regulation in spontaneously hypertensive rats (SHRs). In the present study, we aimed to illustrate the effect of aging on PVAT browning and subsequent vasomotor reaction in SHRs. Herein we utilized histological staining and western blot to detect the characteristics of thoracic PVAT (tPVAT) in 8-week-old and 16-week-old SHR and Wistar-Kyoto (WKY) rats. We also detected vascular reactivity analysis to determine the effect of tPVAT on vasomotor reaction during aging. The results showed that tPVAT had a similar phenotype to BAT, including smaller adipocyte size and positive uncoupling protein-1 (UCP1) staining. Interestingly, the tPVAT of 8-week-old SHR showed increased BAT phenotypic marker expression compared to WKY, whereas the browning level of tPVAT had a more dramatic decrease from 8 to 16 weeks of age in SHR than age-matched WKY rats. The vasodilation effect of tPVAT on aortas had no significant difference in 8-week-old WKY and SHR, whereas this effect is obviously decreased in 16-week-old SHR compared to WKY. In contrast, tPVAT showed a similar vasoconstriction effect in 8- or 16-week-old WKY and SHR rats. Moreover, we identified an important vasodilator adenosine, which regulates adipocyte browning and may be a potential PVAT-derived relaxing factor. Adenosine is dramatically decreased from 8 to 16 weeks of age in the tPVAT of SHR. In summary, aging is associated with a decrease of tPVAT browning and adenosine production in SHR rats. These may result in attenuated vasodilation effect of the tPVAT in SHR during aging.

Pre‐eclampsia (PE) is a life‐threatening multisystem disorder leading to maternal and neonatal mortality and morbidity. Emerging evidence showed that activation of the complement system is implicated in the pathological processes of PE. However, little is known about the detailed cellular and molecular mechanism of complement activation in the development of PE. In this study, we reported that complement 5a (C5a) plays a pivotal role in aberrant placentation, which is essential for the onset of PE. We detected an elevated C5a deposition in macrophages and C5a receptor (C5aR) expression in trophoblasts of pre‐eclamptic placentas. Further study showed that C5a stimulated trophoblasts towards an anti‐angiogenic phenotype by mediating the imbalance of angiogenic factors such as soluble fms‐like tyrosine kinase 1 (sFlt1) and placental growth factor (PIGF). Additionally, C5a inhibited the migration and tube formation of trophoblasts, while, C5aR knockdown with siRNA rescued migration and tube formation abilities. We also found that maternal C5a serum level was increased in women with PE and was positively correlated with maternal blood pressure and arterial stiffness. These results demonstrated that the placental C5a/C5aR pathway contributed to the development of PE by regulating placental trophoblasts dysfunctions, suggesting that C5a may be a novel therapeutic possibility for the disease.

New type of liquid embolic agents based on a liquid crystalline material of glyceryl monooleate (GMO) was developed and evaluated in this study. Ternary phase diagram of GMO, water and ethanol was constructed and three isotropic liquids (ILs, GMO:ethanol:water=49:21:30, 60:20:20 and 72:18:10 (w/w/w)) were selected as potential liquid embolic agents, which could spontaneously form viscous gel cast when contacting with water or physiological fluid. The ILs exhibited excellent microcatheter deliverability due to low viscosity, and were proved to successfully block the saline flow when performed in a device to simulate embolization in vitro. The ILs also showed good cytocompatibility on L929 mouse fibroblast cell line. The embolization of ILs to rabbit kidneys was performed successfully under monitoring of digital subtraction angiography (DSA), and embolic degree was affected by the initial formulation composition and used volume. At 5th week after embolization, DSA and computed tomography (CT) confirmed the renal arteries embolized with IL did not recanalize in follow-up period, and an obvious atrophy of the embolized kidney was observed. Therefore, the GMO-based liquid embolic agents showed feasible and effective to embolize, and potential use in clinical interventional embolization therapy.

Species containing E genome of Thinopyrum offered potential to increase the genetic variability and desirable characters for wheat improvement. However, E genome specific marker was rare. The objective of the present report was to develop and identify sequenced characterized amplified region (SCAR) markers that can be used in detecting E chromosome in wheat background for breeding purpose. Total 280 random amplified polymorphic DNA (RAPD) primers were amplified for seeking of E genome specific fragments by using the genomic DNA of Thinopyrum elongatum and wheat controls as templates. As a result, six RAPD fragments specific for E genome were found and cloned, and then were converted to SCAR markers. The usability of these markers was validated using a number of E- genome-containing species and wheat as controls. These markers were subsequently located on E chromosomes using specific PCR and fluorescence in situ hybridization (FISH). SCAR markers developed in this research could be used in molecular marker assisted selection of wheat breeding with Thinopyrum chromatin introgressions.

Perivascular adipose tissue (PVAT)-derived adiponectin (APN) is a secreted adipokine that protects against hypertension-related cardiovascular injury. However, the regulation of APN expression in hypertension remains to be explored. In this study, we demonstrated that down-regulation of APN was associated with complement activation in the PVAT of desoxycorticosterone acetate (DOCA)-salt hypertensive mice. Complement 3-deficient hypertensive mice were protected from ANP decrease in the PVAT. APN deficiency blockaded the protective effects of complement inhibition against hypertensive vascular injury. Mechanistically, complement 5a (C5a)-induced TNF-α secretion from macrophages is required for inhibiting APN expression in adipocytes. Macrophage depletion reversed C5a agonist peptide-induced TNF-α up-regulation and APN down-regulation in the PVAT of DOCA mice. Moreover, we detected increased macrophage infiltration and C5a expression associated with decreased APN expression in adipose tissue from patients with aldosterone-producing adenoma. These results identify a novel interaction between macrophages and adipocytes in the PVAT, where complement-mediated inhibition of APN acts as a potential risk factor for hypertensive vascular inflammation.-Ruan, C.-C., Ma, Y., Ge, Q., Li, Y., Zhu, L.-M., Zhang, Y., Kong, L.-R., Wu, Q-H., Li, F., Cheng, L., Zhao, A. Z., Zhu, D.-L., Gao, P.-J. Complement-mediated inhibition of adiponectin regulates perivascular inflammation and vascular injury in hypertension.

It was reported previously that rutaecarpine produced a hypotensive effect in phenol-induced and 2-kidney, 1-clip hypertensive rats. However, the same dose of crude rutaecarpine did not produce significant hypotensive effects when applied to spontaneously hypertensive rats (SHR). In the present study, a different dose of rutaecarpine solid dispersion was administered intragastrically to SHR. The systolic blood pressure was monitored by the tail-cuff method with an electro-sphygmomanometer. The plasma concentration of rutaecarpine, calcitonin gene-related peptide (CGRP) and the mRNA levels of CGRP in dorsal root ganglion were determined. The results showed that administration of the solid dispersion significantly increased the blood concentration of rutaecarpine, accompanied by significant hypotensive effects in SHR in a dose-dependent manner. The levels of plasma CGRP were also elevated significantly, concomitantly with the increased mRNA levels in the dorsal root ganglion in a dose-dependent manner. It was concluded that a change of the dosage from the crude drug to solid dispersion could improve significantly the efficiency of rutaecarpine absorption and increase its plasma concentration. The anti-hypertensive effect exerted by rutaecarpine solid dispersion in SHR is mediated by CGRP.

The mutagenic potential of leachates derived from the bottom ash of a municipal solid waste incinerator in Taiwan were evaluated using an Ames Salmonella mutagenicity assay with three standard tester strains, TA98, TA100, and TA1535. Three types of leachants, leachant A (pH 4.93), leachant B (pH 2.88), and leachant C (deionized water, pH 6.0), were carried out according to toxicity characteristic leaching procedure (TCLP). Moreover, two types of bottom ash, nonsieved and sieved bottom ash (particle size

The zygomycete fungus Blakeslea trispora is usually used as a natural source of lycopene and β-carotene. In this study, the B. trispora (-) strain, a major mating type for lycopene production, was treated with N(+) ion implantation and N-methyl-N'-nitro-N-nitrosoguanidine (NTG), and further isolated on the screening plates supplemented with lovastatin and crude extracts of trisporic acid (CTA). After several rounds of screening, four mutants with higher yield of lycopene and biomass were isolated. Among these mutants, I5 obtained with N(+) ion implantation showed a maximum lycopene yield (28.8 mg/g), which was 64 % higher than the parent strain (17.5 mg/g) in the production of lycopene. The results indicated that N(+) ion implantation is more suitable for B. trispora (-) than NTG treatment, and the addition of lovastatin promoted the generation of positive mutant and CTA amplified the color differences between colonies.