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Hutchinson–Gilford progeria syndrome (HGPS) is an ultrarare and fatal disease with features of premature aging and cardiovascular diseases (atherosclerosis, myocardial infarction, and stroke). Several landmark studies in 2018–2019 have revealed novel mechanisms underlying cardiovascular pathologies in HGPS, and implicate future potential therapies for HGPS, and possibly physiological aging. [ABSTRACT FROM AUTHOR]

P-glycoprotein (P-gp) affects the transport of many drugs; including puerarin and vincristine. Our previous study demonstrated that imperatorin increased the intestinal absorption of puerarin and vincristine by inhibiting P-gp-mediated drug efflux. However; the underlying mechanism was not known. The present study investigated the mechanism by which imperatorin promotes P-gp-mediated drug transport. We used molecular docking to predict the binding force between imperatorin and P-gp and the effect of imperatorin on P-gp activity. P-gp efflux activity and P-gp ATPase activity were measured using a rhodamine 123 (Rh-123) accumulation assay and a Pgp-Glo™ assay; respectively. The fluorescent probe 1,6-diphenyl-1,3,5-hexatriene (DPH) was used to assess cellular membrane fluidity in MDCK-MDR1 cells. Western blotting was used to analyze the effect of imperatorin on P-gp expression; and P-gp mRNA levels were assessed by qRT-PCR. Molecular docking results demonstrated that the binding force between imperatorin and P-gp was much weaker than the force between P-gp and verapamil (a P-gp substrate). Imperatorin activated P-gp ATPase activity; which had a role in the inhibition of P-gp activity. Imperatorin promoted Rh-123 accumulation in MDCK-MDR1 cells and decreased cellular membrane fluidity. Western blotting demonstrated that imperatorin inhibited P-gp expression; and qRT-PCR revealed that imperatorin down-regulated P-gp (MDR1) gene expression. Imperatorin decreased P-gp-mediated drug efflux by inhibiting P-gp activity and the expression of P-gp mRNA and protein. Our results suggest that imperatorin could down-regulate P-gp expression to overcome multidrug resistance in tumors. [ABSTRACT FROM AUTHOR]

The effect of three major influence process parameters, carbon addition ratio, ore particle size, and coal particle size on the compressive strength of high-alumina iron ore-coal composite hot briquette (Al-CCB) with the application of response surface methodology is investigated in this paper. The results show that, with using multiple regression analysis, the experimental data can be fitted into a quadratic polynomial model. Based on the coefficient of determination ( R2 = 0.9883) and the analysis of variance (ANOVA), the model shows good agreement with the experimental data. The effect on the compressive strength of Al-CCB from big to small is carbon addition ratio, ore particle size, and coal particle size. In order to obtain the Al-CCB with 600 N of compressive strength, the optimal experiment conditions are found to be the coal addition ratio of 16.44%, ore particle size of −100 mesh and coal particle size of −100 mesh, resulting in an actual compressive strength of 613 N, as compared to the model prediction of 600 N. This paper can provide guidance for the optimization on preparation of Al-CCB. Also, it can offer reference for the process improvement of other ore-coal composite agglomerates. [ABSTRACT FROM AUTHOR]

Chronic stress alters the hypothalamic–pituitary–adrenal (HPA) axis and enhances visceral and somatosensory pain perception. It is unresolved whether chronic stress has distinct effects on visceral and somatosensory pain regulatory pathways. Previous studies reported that stress-induced visceral hyperalgesia is associated with reciprocal alterations of endovanilloid and endocannabinoid pain pathways in DRG neurons innervating the pelvic viscera. In this study, we compared somatosensory and visceral hyperalgesia with respect to differential responses of peripheral pain regulatory pathways in a rat model of chronic, intermittent stress. We found that chronic stress induced reciprocal changes in the endocannabinoid 2-AG (increased) and endocannabinoid degradation enzymes COX-2 and FAAH (decreased), associated with down-regulation of CB1 and up-regulation of TRPV1 receptors in L6–S2 DRG but not L4–L5 DRG neurons. In contrast, sodium channels Na v 1.7 and Na v 1.8 were up-regulated in L4–L5 but not L6–S2 DRGs in stressed rats, which was reproduced in control DRGs treated with corticosterone in vitro. The reciprocal changes of CB1, TRPV1 and sodium channels were cell-specific and observed in the sub-population of nociceptive neurons. Behavioral assessment showed that visceral hyperalgesia persisted, whereas somatosensory hyperalgesia and enhanced expression of Na v 1.7 and Na v 1.8 sodium channels in L4–L5 DRGs normalized 3 days after completion of the stress phase. These data indicate that chronic stress induces visceral and somatosensory hyperalgesia that involves differential changes in endovanilloid and endocannabinoid pathways, and sodium channels in DRGs innervating the pelvic viscera and lower extremities. These results suggest that chronic stress-induced visceral and lower extremity somatosensory hyperalgesia can be treated selectively at different levels of the spinal cord. [ABSTRACT FROM AUTHOR]

A novel, rapid and cheap amperometric immunosensor was described for the detection of E. coli O157:H7 . First, the four-layer functionalised magnetic nanoparticle was prepared with a Fe 3 O 4 magnetic core, a Prussian blue (PB) and N-(2-aminoethyl)-3-aminopropyltrimethoxysilane (AEAPS) interlayer and an Au nanoparticles shell (denoted as Au-AEAPS-PB-Fe 3 O 4 ). Next, the immunomagnetic anti- E. coli O157:H7 /Au-AEAPS-PB-Fe 3 O 4 beads were prepared through the Au-SH bond between the antibodies of E. coli O157:H7 (anti- E. coli O157:H7 ) and Au-AEAPS-PB-Fe 3 O 4 . After that step, the immunomagnetic beads were coated on the designed electrifying controllable magnetic electrode (ECME) surface using an internal electromagnet to turn on the electricity supply (dry cell) for electrochemical immunosensing fabrication. The experimental results show that the Au-AEAPS-PB-Fe 3 O 4 nanoparticles exhibit satisfying redox electrochemical activity; the linear range of heat-killed E. coli O157:H7 was from 3.6 × 10 3 to 3.6 × 10 6 cfu mL −1 . Furthermore, this immunosensor could be regenerated by simply turning off the electricity supply. Importantly, a single system was illustrated with E. coli O157:H7 , and we expect that the proposed system with an amperometric immunosensor is suitable for use in the detection of other pathogens. [ABSTRACT FROM AUTHOR]

With the increasing number of underwater pipeline investigation activities, the research on automatic pipeline detection is of great significance. At this stage, object detection algorithms based on Deep Learning (DL) are widely used due to their abilities to deal with various complex scenarios. However, DL algorithms require massive representative samples, which are difficult to obtain for pipeline detection with sub-bottom profiler (SBP) data. In this paper, a zero-shot pipeline detection method is proposed. First, an efficient sample synthesis method based on SBP imaging principles is proposed to generate samples. Then, the generated samples are used to train the YOLOv5s network and a pipeline detection strategy is developed to meet the real-time requirements. Finally, the trained model is tested with the measured data. In the experiment, the trained model achieved a mAP@0.5 of 0.962, and the mean deviation of the predicted pipeline position is 0.23 pixels with a standard deviation of 1.94 pixels in the horizontal direction and 0.34 pixels with a standard deviation of 2.69 pixels in the vertical direction. In addition, the object detection speed also met the real-time requirements. The above results show that the proposed method has the potential to completely replace the manual interpretation and has very high application value. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Angelicae Dahurica(Hoffm.)Benth.&Hook.f.ex Franch.&Sav combined with Scutellaria baicalensis Georgi. has been widely used as herb-pairs in traditional Chinese medicine (TCM) to treat migraine headache and cataract, but the underlying compatibility mechanism of the two herbs remains unknown. Aim of study: In the present work, we investigated the additive or synergistic effects of absorption behavior of Radix Angelicae dahuricae extracts on baicalin, and the absorption-enhancing mechanism of Radix Angelicae dahuricae extracts on baicalin. Materials and methods: Total coumarins (Cou) and volatile oil (VO), as the two main components of Radix Angelicae dahuricae, were extracted by supercritical fluid extraction (SFE) further treated with liquid–liquid separation method. The absorption behavior was investigated by applying the everted gut sac technique and in situ single-pass intestinal perfusion method. Results and conclusions: The results showed that both the Cou and the VO could improve the intestinal absorption of baicalin in vivo, and had synergistic action the enhanced absorption of baicalin. Since verapamil did not affect the P app and K a of baicalin significantly, we concluded that the absorption of Baicalin could not be an active transportation in dependent of P-glycoprotein-Mediated efflux systems. Based on intestinal absorption of drug studying was one of the efficacious methods to clarify the compatibility of principles of herb-pairs. The everted gut sac technique and in situ single-pass intestinal perfusion technique model were the effective methods to study the absorption of drug, the application of the animal model to investigating the absorption of herb–drug interactions or other relevant research purposes is envisioned. [Copyright &y& Elsevier]

Carbon composite iron ore hot briquette (CCB) is the product of fine iron ore and fine coal by hot briquetting process, which attracts more and more attention as a new type of ironmaking raw materials aiming to improve the operation efficiency and reduce the coke consumption of blast furnace. This paper is devoted to experimental study on metallurgical properties of CCB and numerical simulation of the BF operation with CCB charging. At first, the metallurgical properties of CCB, including cold crushing strength, RDI, RSI, reducibility, high temperature strength, and softening and dripping are experimentally tested and compared with the common burdens, which revealed that the CCB possesses the required metallurgical properties and is suitable to use as the blast furnace burden. Then, the effects of charging CCB on the dripping properties of comprehensive burdens are elucidated based on the experiments under simulated blast furnace conditions. The results showed that the maximum charging ratio of CCB in the iron burdens is 40%-50% for achieving appropriate dripping properties of the mixed burdens. Finally, a multi-fluid blast furnace model is used to simulate BF operation with CCB charging. According to model simulations, charging CCB will cause the temperature level to decreases in the furnace and the location of the cohesive zone shifts downward. On the other hand, the productivity tends to increase while coke rate and total reducing agent rate decrease, the heat efficiency improves remarkably and the operation performance of BF is effectively enhanced. [ABSTRACT FROM AUTHOR]

Aim of study: Yuanhu Zhitong prescription that consists of Corydalis yanhusuo and Radix Angelicae dahuricae has been used for the treatment of gastralgia, costalgia, headache and dysmenorrhea in Traditional Chinese Medicine. Our previous studies demonstrated that Corydalis alkaloid (CA, derived from the root of Corydalis yanhusu) had potent analgesic properties, and the total coumarins of Angelica dahurica (Cou) and volatile oil (VO) that derived from the root of Radix Angelicae dahuricae all could increase the analgesic effect of CA. The major objective of this paper was to investigate the mechanism that leading the analgesia of CA increased by Cou and (or) VO. Materials and methods: : The relationship between analgesic effect of CA and the plasma concentration of Dl-tetrahydropalmatine (dl-THP, active component of CA) was assayed in mice writhing test. The CA (34, 68 and 134mg/kg) reduced the nociception by acetic acid intraperitoneal injection in a dose-dependent manner, and there was a significant linear relationship between the analgesic effect of CA and the plasma concentration of dl-THP. Then the plasma concentration of dl-THP at different time intervals in rats after oral administration of CA, CA–Cou, CA–VO and CA–Cou–VO were examined by using HPLC. Results and conclusion: : The results indicated that Cou and (or) VO raised the plasma concentration of dl-THP prominently. In conclusion, the reason that Radix Angelica dahurica extracts reinforced the analgesic effects of Corydalis alkaloid was related to the improvement of the plasma concentration of dl-THP. [Copyright &y& Elsevier]

Abstract: A screening experiment with fractional factorial design and response surface methodology (RSM) with Box-Behnken design (BBD) was used to optimize the microwave-assisted extraction (MAE) of Yuanhu Zhitong (YZ) prescription. The optimum operating conditions were finally obtained by using a desirability function. A 26−2 fractional factorial design was initially employed and it was found that microwave power, extraction time, ethanol level and extraction times were the most important variables that affected the yield of tetrahydropalmatine, imperatorin and isoimperatorin, which are active components in YZ prescription. Results show that the optimal conditions were microwave power of 500W, ethanol level of 70% and extraction time was 27min. The extraction yield of tetrahydropalmatine, imperatorin and isoimperatorin was 85.4%, 104.0% and 113.6%, respectively, and the yield of extracta sicca was 10.4%. [Copyright &y& Elsevier]

Abstract: Glial activation is known to contribute to pain hypersensitivity following spinal sensory nerve injury. In this study, we investigated mechanisms by which glial cell activation in medullary dorsal horn (MDH) would contribute to tactile hypersensitivity following inferior alveolar nerve and mental nerve transection (IAMNT). Activation of microglia and astrocytes was monitored at 2h, 1, 3, 7, 14, 28, and 60 days using immunohistochemical analysis with OX-42 and GFAP antibodies, respectively. Tactile hypersensitivity was significantly increased at 1 day, and this lasted for 28 days after IAMNT. Microglial activation, primarily observed in the superficial laminae of MDH, was initiated at 1 day, maximal at 3 days, and maintained until 14 days after IAMNT. Astrocytic activation was delayed compared to that of microglia, being more profound at 7 and 14 days than at 3 days after IAMNT. Both tactile hypersensitivity and glial activation appeared to gradually reduce and then return to the basal level by 60 days after IAMNT. There was no significant loss of trigeminal ganglion neurons by 28 days following IAMNT, suggesting that degenerative changes in central terminals of primary afferents might not contribute to glial activation. Minocycline, an inhibitor of microglial activation, reduced microglial activation, inhibited p38 mitogen-activated protein kinase (MAPK) activation in microglia, and significantly attenuated the development of pain hypersensitivity in this model. These results suggest that glial activation in MDH plays an important role in the development of neuropathic pain and activation of p38 MAPK in hyperactive microglia contributes to pain hypersensitivity in IAMNT model. [Copyright &y& Elsevier]

Vascular endothelial growth factor (VEGF) is essential for many angiogenic processes both in normal conditions and in pathological conditions. However, the signaling pathways involved in VEGF-induced angiogenesis are not well defined. Protein kinase D (PKD), a newly described serine/threonine protein kinase, has been implicated in many signal transduction pathways and in cell proliferation. We hypothesized that PKD would mediate VEGF signaling and function in endothelial cells. Here we found that VEGF rapidly and strongly stimulated PKD phosphorylation and activation in endothelial cells via VEGF receptor 2 (VEGFR2). The pharmacological inhibitors for phospholipase Cγ (PLCγ) and protein kinase C (PKC) significantly inhibited VEGF-induced PKD activation, suggesting the involvement of the PLCγ/PKC pathway. In particular, PKCα was critical for VEGF-induced PKD activation since both overexpression of adenovirus PKCα dominant negative mutant and reduction of PKCα expression by small interfering RNA markedly inhibited VEGF-induced PKD activation. Importantly, we found that small interfering RNA knockdown of PKD and PKCα expression significantly attenuated ERK activation and DNA synthesis in endothelial cells by VEGF. Taken together, our results demonstrated for the first time that VEGF activates PKD via the VEGFR2/PLCγ/PKCα pathway and revealed a critical role of PKD in VEGF-induced ERK signaling and endothelial cell proliferation. [ABSTRACT FROM AUTHOR]

Fluid shear stress generated by blood flow modulates endothelial cell function via specific intracellular signaling events. We showed previously that flow activated the phosphatidylinositol 3-kinase (PI3K), Akt, and endothelial nitric-oxide synthase (eNOS) via Src kinase-dependent teansactivation of vascular endothelial growth factor receptor 2 (VEGFR2). The scaffold protein Gab1 plays an important role in receptor tyrosine kinase-mediated signal transduction. We found here that laminar flow (shear stress = 12 dynes/cm2) rapidly stimulated Gab1 tyrosine phosphorylation in both bovine aortic endothelial cells and human umbilical vein endothelial cells, which correlated with activation of Akt and eNOS. Gab1 phosphorylation as well as activation of Akt and eNOS by flow was inhibited by the Src kinase inhibitor PP2 (4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine) and VEGFR2 kinase inhibitors SU1498 and VTI, suggesting that flow-mediated Gab1 phosphorylation is Src kinase-dependent and VEGFR2-dependent. Tyrosine phosphorylation of Gab1 by flow was functionally important, because flow stimulated the association of Gab1 with the PI3K subunit p85 in a time-dependent manner. Furthermore, transfection of a Gab1 mutant lacking p85 binding sites inhibited flow-induced activation of Akt and eNOS. Finally, knockdown of endogenous Gab1 by small interference RNA abrogated flow activation of Akt and eNOS. These data demonstrate a critical role of Gab1 in flow-stimulated PI3K/Akt/eNOS signal pathway in endothelial cells. [ABSTRACT FROM AUTHOR]

Fluid shear stress generated by blood flowing over the endothelium is a major determinant of arterial tone, vascular remodeling, and atherogenesis. Nitric oxide (NO) produced by endothelial NO synthase (eNOS) plays an essential role in regulation of vascular function and structure by blood flow. Although cyclosporin A (CsA), an inhibitory ligand of cyclophilin A, is a widely used immunosuppressive drug, it causes arterial hypertension in part by impairing eNOS-dependent vasodilation. Here we show that CsA inhibits fluid shear stress-mediated eNOS activation in endothelial cells via decreasing cholesterol content in caveolae. Exposure of cultured bovine aortic endothelial cells to 1 μM CsA for 1 h significantly inhibited NO production and eNOS phosphorylation at Ser-1179 induced by flow (shear stress = 12 dynes/cm2). The effect of CsA was not related to inhibition of two known eNOS kinases, protein kinase B (Akt) and protein kinase A, because CsA did not affect Akt or protein kinase A activation. In rabbit aorta perfused ex vivo, CsA also significantly inhibited flow-induced eNOS phosphorylation at Ser-1179 but had no effect on Akt measured by phosphorylation at Ser-473. However, CsA treatment decreased cholesterol content in caveolae and displaced eNOS from caveolae, which may be caused by CsA disrupting the association of caveolin-1 and cyclophilin A. The magnitude of the cholesterol depleting effect was similar to that of β-cyclodextrin, a cholesterol-binding molecule, and β-cyclodextrin had a similar inhibitory effect on flow-mediated eNOS activation. Treating bovine aortic endothelial cells for 24 h with 30 μg/ml cholesterol blocked the CsA effect and restored eNOS phosphorylation in response to flow. These data suggest that decreasing cholesterol content in caveolae by CsA is a potentially important pathogenic mechanism for CsA-induced endothelial dysfunction and hypertension. [ABSTRACT FROM AUTHOR]

Until 30 years ago, it had been considered that D-amino acids were excluded from living systems except for D-amino acids in the cell wall of microorganisms. However, D-amino acids, in the form of free amino acids, peptides and proteins, were recently detected in various living organisms from bacteria to mammals. The extensive distribution of bio-functional D-amino acids challenges the current concept of protein synthesis: more attention should be paid to the stereospecificity of the translation machine. Besides aminoacyl-tRNA synthetases, elongation factor Tu and some other mechanisms, D-Tyr-tRNATyr deacylases provide a novel checkpoint since they specifically recycle misaminoacylated D-Tyr-tRNATyr and some other D-aminoacyl-tRNAs. Their unique structure represents a new class of tRNA-dependent hydrolase. These unexpected findings have far-reaching implications for our understanding of protein synthesis and its origin. [Copyright &y& Elsevier]

We investigated the effects of a GABAB agonist baclofen, and serotonin, on the high voltage-activated Ca channel (HVACC) currents in trigeminal motoneurons. Immunohistochemical and reverse transcription-polymerization chain reaction (RT-PCR) studies demonstrated the expression of α1C, α1B, α1A, and α1E subunits in the trigeminal motoneurons, which form L-, N-, P/Q-, and R-type Ca channels, respectively. By use of specific Ca blockers, it was found that N-type (38%), P/Q-type (27%), L-type (16 %), and R-type Ca currents (19%) contribute to HVACC IBa. Baclofen inhibited HVACC IBa in the majority of trigeminal motoneurons tested (n=15 out of 16), whereas serotonin only did in a small population (n=5 out of 18). The IBa inhibition by baclofen and serotonin was associated with slowing of activation kinetics, relieved by strong prepulse, and prevented by N-ethylmaleimide (NEM), indicative of mediation of Gi/Go. These data provide evidence that GABAergic and serotonergic inputs to trigeminal motoneurons regulate neuronal activities through the inhibition of HVACC currents. [Copyright &y& Elsevier]

Determining the altitude of side-scan sonar (SSS) above the seabed is critical to correct the geometric distortions in the sonar images. Usually, a technology named bottom tracking is applied to estimate the distance between the sonar and the seafloor. However, the traditional methods for bottom tracking often require pre-defined thresholds and complex optimization processes, which make it difficult to achieve ideal results in complex underwater environments without manual intervention. In this paper, a universal automatic bottom tracking method is proposed based on semantic segmentation. First, the waterfall images generated from SSS backscatter sequences are labeled as water column (WC) and seabed parts, then split into specific patches to build the training dataset. Second, a symmetrical information synthesis module (SISM) is designed and added to DeepLabv3+, which not only weakens the strong echoes in the WC area, but also gives the network the capability of considering the symmetry characteristic of bottom lines, and most importantly, the independent module can be easily combined with any other neural networks. Then, the integrated network is trained with the established dataset. Third, a coarse-to-fine segmentation strategy with the well-trained model is proposed to segment the SSS waterfall images quickly and accurately. Besides, a fast bottom line search algorithm is proposed to further reduce the time consumption of bottom tracking. Finally, the proposed method is validated by the data measured with several commonly used SSSs in various underwater environments. The results show that the proposed method can achieve the bottom tracking accuracy of 1.1 pixels of mean error and 1.26 pixels of standard deviation at the speed of 2128 ping/s, and is robust to interference factors. [ABSTRACT FROM AUTHOR]

Cytoglobin (Cygb) is a globin molecule that is ubiquitously expressed in all tissues and has a protective role under oxidative stress. It has also been demonstrated to be effective in the treatment of alcoholic fatty liver disease (AFLD). In order to study the molecular mechanisms underlying its beneficial effects for the treatment of alcoholic liver, two-dimensional electrophoresis and mass spectrometric analysis were performed on serum and liver tissues from an in vivo rat model of AFLD. A total of 26 differentially expressed proteins were identified in the serum and 20 differentially expressed proteins were identified in liver specimens. Using online bioinformatics tools, it was indicated that these differentially expressed proteins were primarily associated with pathways including binding and uptake of ligands by scavenger receptors, response to corticosteroid, plasma lipoprotein remodeling, regulation of complement cascade, hydrogen peroxide catabolic process, as well as response to nutrient and monosaccharide. The present results suggested that recombinant human Cygb exerts its role in the treatment of AFLD primarily through affecting nutrient metabolism, monocarboxylic acid biosynthesis, regulation of glutathione expression, plasma lipoprotein remodeling and removal of metabolic waste from the blood. [ABSTRACT FROM AUTHOR]

Multidrug resistance of tumors has been a severe obstacle to the success of cancer chemotherapy. The study wants to investigate the reversal effects of imperatorin (IMP) on doxorubicin (DOX) resistance in K562/DOX leukemia cells, A2780/Taxol cells and in NOD/SCID mice, to explore the possible molecular mechanisms. K562/DOX and A2780/Taxol cells were treated with various concentrations of DOX and Taol with or without different concentrations of IMP, respectively. K562/DOX xenograft model was used to assess anti-tumor effect of IMP combined with DOX. MTT assay, Rhodamine 123 efflux assay, RT-PCR, and Western blot analysis were determined in vivo and in vitro. Results showed that IMP significantly enhanced the cytotoxicity of DOX and Taxol toward corresponding resistance cells. In vivo results illustrated both the tumor volume and tumor weight were significantly decreased after 2-week treatment with IMP combined with DOX compared to the DOX alone group. Western blotting and RT-PCR analyses indicated that IMP downregulated the expression of P-gp in K562/DOX xenograft tumors in NOD/SCID mice. We also evaluated glycolysis and glutamine metabolism in K562/DOX cells by measuring glucose consumption and lactate production. The results revealed that IMP could significantly reduce the glucose consumption and lactate production of K562/DOX cells. Furthermore, IMP could also remarkably repress the glutamine consumption, α-KG and ATP production of K562/DOX cells. Thus, IMP may sensitize K562/DOX cells to DOX and enhance the antitumor effect of DOX in K562/DOX xenograft tumors in NOD/SCID mice. IMP may be an adjuvant therapy to mitigate the multidrug resistance in leukemia chemotherapy. [ABSTRACT FROM AUTHOR]

Inflammatory response in the pulmonary endothelium drives the pathogenesis of acute lung injury and sepsis. Sirtuin 6 (SIRT6), a member of class III NAD+-dependent deacetylases belonging to the sirtuin family, regulates senescence, metabolism, and inflammation and extends lifespan in mice and model organisms. However, the role of SIRT6 in pulmonary endothelial inflammation is unknown. Thus, we hypothesized that SIRT6 suppresses inflammatory response in human lung microvascular cells (HLMEC) and ensues monocyte adhesion to endothelial cells. Primary HLMECs were treated with control or SIRT6 adenovirus or SIRT6 agonist, with or without lipopolysaccharide (LPS) treatment. We observed that treatment with LPS did not affect the protein expression of SIRT6 in HLMECs. However, adenovirus-mediated SIRT6 overexpression attenuated LPS-induced VCAM1 gene and protein expression, followed by decreased monocyte adhesion to endothelial cells. Similarly, activation of SIRT6 by a recently reported SIRT6 activator UBCS039, but not the regioisomer negative control compound UBCS060, ameliorated LPS-induced VCAM1 mRNA and protein expression as well as monocyte adhesion. Moreover, luciferase assay revealed that SIRT6 adenovirus decreased the activity of NF-κB, the master regulator of vascular inflammation. Taken together, these results indicate that molecular and pharmacological activation of SIRT6 protects against lung microvascular inflammation via suppressing NF-κB activation, implicating the therapeutic potential of the SIRT6 activators for lung disorders associated with microvascular inflammation. [ABSTRACT FROM AUTHOR]

Background: Chronic stress is associated with activation of the HPA axis, elevation in pro‐inflammatory cytokines, decrease in intestinal epithelial cell tight junction (TJ) proteins, and enhanced visceral pain. It is unknown whether epigenetic regulatory pathways play a role in chronic stress–induced intestinal barrier dysfunction and visceral hyperalgesia. Methods: Young adult male rats were subjected to water avoidance stress ± H3K9 methylation inhibitors or siRNAs. Visceral pain response was assessed. Differentiated Caco‐2/BBE cells and human colonoids were treated with cortisol or IL‐6 ± antagonists. Expression of TJ, IL‐6, and H3K9 methylation status at gene promoters was measured. Transepithelial electrical resistance and FITC‐dextran permeability were evaluated. Key Results: Chronic stress induced IL‐6 up‐regulation prior to a decrease in TJ proteins in the rat colon. The IL‐6 level inversely correlated with occludin expression. Treatment with IL‐6 decreased occludin and induced visceral hyperalgesia. Chronic stress and IL‐6 increased H3K9 methylation and decreased transcriptional GR binding to the occludin gene promoter, leading to down‐regulation of protein expression and increase in paracellular permeability. Intrarectal administration of a H3K9 methylation antagonist prevented chronic stress–induced visceral hyperalgesia in the rat. In a human colonoid model, cortisol decreased occludin expression, which was prevented by the GR antagonist RU486, and IL‐6 increased H3K9 methylation and decreased TJ protein levels, which were prevented by inhibitors of H3K9 methylation. Conclusions & Inferences: Our findings support a novel role for methylation of the repressive histone H3K9 to regulate chronic stress, pro‐inflammatory cytokine–mediated reduction in colon TJ protein levels, and increase in paracellular permeability and visceral hyperalgesia. [ABSTRACT FROM AUTHOR]

A series of dinuclear platinum(II) alkynyl complexes [Pt2L2(C≡CC6H4R-4)4] (R = H 1, CH32, But3) and unusual tetranuclear Pt(II)–Ag(I) clusters [Pt2Ag2L(C≡CC6H4R-4)6] (R = H, 4; CH3, 5; But, 6), together with novel polymer crystals [Pt2Ag2L(C≡CC6H5)6]∞ ([4]∞), were synthesized by a self-assembly reaction between [NBu4]2[Pt(C≡CC6H4-R-4)4] and [Ag6L6]6+ (L = 4-(3,5-(diphenylphosphine)phenyl)pyridine). These complexes were characterized by using a range of spectroscopic techniques and complexes 1, 3, 5, and [4]∞ were analysed by X-ray crystallography. Each platinum atom of the Pt(II)–Ag(I) clusters shows an unusual asymmetric distorted square planar geometry with three alkynyl groups and one bridging L phosphorus atom. Dinuclear complexes 1–3 demonstrate solid-state weak blue luminescence, while tetranuclear Pt(II)–Ag(I) clusters 4–6 show intense blue-green or yellow-green emission. Furthermore, the crystalline samples of polymer [4]∞ display bright yellow emission (518 nm) that is significantly red-shifted as compared to monomer crystal 4. [ABSTRACT FROM AUTHOR]

Background: Src-associated in mitosis (Sam68; 68 kDa) has been implicated in the oncogenesis and progression of several human cancers. The aim of this study was to investigate the clinicopathologic significance of Sam68 expression and its subcellular localization in colorectal cancer (CRC).Methods: Sam68 expression was examined in CRC cell lines, nine matched CRC tissues and adjacent noncancerous tissues using reverse transcription (RT)-PCR, quantitative RT-PCR and Western blotting. Sam68 protein expression and localization were determined in 224 paraffin-embedded archived CRC samples using immunohistochemistry. Statistical analyses were applied to evaluate the clinicopathologic significance.Results: Sam68 was upregulated in CRC cell lines and CRC, as compared with normal tissues; high Sam68 expression was detected in 120/224 (53.6%) of the CRC tissues. High Sam68 expression correlated significantly with poor differentiation (P = 0.033), advanced T stage (P < 0.001), N stage (P = 0.023) and distant metastasis (P = 0.033). Sam68 nuclear localization correlated significantly with poor differentiation (P = 0.002) and T stage (P =0.021). Patients with high Sam68 expression or Sam68 nuclear localization had poorer overall survival than patients with low Sam68 expression or Sam68 cytoplasmic localization. Patients with high Sam68 expression had a higher risk of recurrence than those with low Sam68 expression.Conclusions: Overexpression of Sam68 correlated highly with cancer progression and poor differentiation in CRC. High Sam68 expression and Sam68 nuclear localization were associated with poorer overall survival. [ABSTRACT FROM AUTHOR]

Atherosclerosis is a chronic inflammatory and lipid-depository disease that eventually leads to acute cardiovascular events. Emerging evidence supports that epigenetic processes such as DNA methylation, histone modification, and noncoding RNAs play an important role in plaque progression and vulnerability, highlighting the therapeutic potential of epigenetic drugs in cardiovascular therapeutics. [ABSTRACT FROM AUTHOR]

ε-Poly- l -lysine (ε-PL) serves as a biological preservative in food industry for many years in several countries. However, the naturally occurring ε-PL with the chain length of 25–35 l -lysine residuals exhibits bitter taste. Thus, the decrease of chain length at an appropriate range has become very critical for the wide application of ε-PL. Herein, we proposed an efficient strategy for the short chain ε-PL production with the high yield (39.84 g/L), high purity (98.81%) and high recovery ratio (72.59%) by fed-batch fermentation using glycerol as carbon source. The short chain ε-PL with 8–32 l -lysine residuals showed different secondary structures and better antimicrobial activity towards yeast than naturally occurring one. As a result, a simple, low-cost and safe strategy for high-level production of short chain ε-PL was developed, which may enlarge the application of ε-PL in the food industry. [ABSTRACT FROM AUTHOR]

Background: Our recent studies found that intestinal mechanical signals can regulate mucus synthesis and secretion of intestinal goblet cells through piezo type mechanosensitive ion channel component 1 (Piezo1), but the detailed molecular mechanisms remain to be investigated. Previous studies using a water avoidance stress (WAS) model reported decreased intestinal mucus accompanied by abnormal intestinal motility. It has also been reported that the expression of mucin2 was negatively correlated with histone H3 lysine 9 trimethylation (H3K9me3), a key regulator of histone methylation, and that mechanical stimulation can affect methylation. In this study, we aimed to determine whether and how Piezo1 expressed on goblet cells regulates mucus barrier function through methylation modification. Methods: A murine WAS model was established and treated with Yoda1 (Piezo1 agonist), and specific Piezo1 flox-mucin2 Cre mice were also tested. The mucus layer thickness and mucus secretion rate of mouse colonic mucosa were detected by a homemade horizontal Ussing chamber, intestinal peristaltic contraction was detected by the ink propulsion test and organ bath, goblet cells and mucus layer morphology were assessed by HE and Alcian blue staining, mucus permeability was detected by FISH, and the expression levels of Piezo1, H3K9me3 and related molecules were measured by Western blots and immunofluorescence. LS174T cells were cultured on a shaker board in vitro to simulate mechanical stimulation. Piezo1 and H3K9me3 were inhibited, and changes in mucin2 and methylation-related pathways were detected by ELISAs and Western blots. ChIP-PCR assays were used to detect the binding of H3K9me3 and mucin2 promoters under mechanical stimulation. Results: Compared with those of the controls, the mucus layer thickness and mucus secretion rate of the mice exposed to WAS were significantly decreased, the mucus permeability increased, the number of goblet cells decreased, and the intestinal contraction and peristalsis were also downregulated and disordered. Intraperitoneal injection of Yoda1 improved mucus barrier function and intestinal contraction. In the colonic mucosa of mice exposed to WAS, Piezo1 was decreased, and histone H3 lysine 9 trimethylation (H3K9me3) and methyltransferase suppressor of variegation 3–9 homolog 1 (SUV39h1) were increased, but activating Piezo1 alleviated these effects of WAS. Piezo1 flox-mucin2 Cre mice showed decreased mucus expression and increased methylation compared to wild-type mice. Cell experiments showed that mechanical stimulation induced the activation of Piezo1, decreased H3K9me3 and SUV39h1, and upregulated mucin2 expression. Inhibition of Piezo1 or H3K9me3 blocked the promoting effect of mechanical stimulation on LS174T mucin2 expression. The binding of H3K9me3 to the mucin2 promoter decreased significantly under mechanical stimulation, but this could be blocked by the Piezo1 inhibitor GsMTx4. Conclusion: Piezo1 mediates mechanical stimulation to inhibit SUV39h1, thereby reducing H3K9me3 production and its binding to the mucin2 promoter, ultimately promoting mucin2 expression in goblet cells. This study further confirmed that piezo1 on goblet cells could regulate mucus barrier function through methylation. [ABSTRACT FROM AUTHOR]

Oxadiazoles (II) are synthesized by anodic oxidation of benzoyl hydrazines (I). [ABSTRACT FROM AUTHOR]

The four heteronuclear clusters [Ag2Au2(μ-dpppy)3(CCC6H4R-4)2](ClO4)2(R = H (1) CH3(2), COOCH3(3), CHO (4)) were prepared bythe self-assembly reaction between (AuCC6H4R-4)n(R = H, CH3,COOCH3, CHO) and [Ag2(μ-dpppy)3]2+(dpppy = 2,6-bis(diphenylphosphino)pyridine)and characterized by elemental analyses, electrospray ionization massspectrometry (ESI-MS), and 1H NMR and 31P{1H} NMR spectroscopy and by X-ray crystallography for 1, 3, and 4. It is revealed thatthe complexes exhibit bright blue (1–3) and green (4) luminescence in the solid state andin solution with the luminescent lifetimes in the microsecond range,indicating that the luminescence is most likely associated with aspin-forbidden triplet parentage. Interestingly, only complex 4displays distinctly mechanical grinding responsive emissionswitching. The recognition interactions of complex 4containingaldehyde groups with homocysteine (Hcy) and cysteine (Cys) have beenstudied by UV–vis and emission titrations. A strong luminescencequench was found upon reaction of complex 4only withHcy or Cys, but not with other amino acids, proteins, and common anions,indicating a high specificity for recognition of Hcy and Cys. [ABSTRACT FROM AUTHOR]

Background: Src-associated in mitosis (Sam68; 68 kDa) has been implicated in the oncogenesis and progression of several human cancers. The aim of this study was to investigate the clinicopathologic significance of Sam68 expression and its subcellular localization in colorectal cancer (CRC). Methods: Sam68 expression was examined in CRC cell lines, nine matched CRC tissues and adjacent noncancerous tissues using reverse transcription (RT)-PCR, quantitative RT-PCR and Western blotting. Sam68 protein expression and localization were determined in 224 paraffin-embedded archived CRC samples using immunohistochemistry. Statistical analyses were applied to evaluate the clinicopathologic significance. Results: Sam68 was upregulated in CRC cell lines and CRC, as compared with normal tissues; high Sam68 expression was detected in 120/224 (53.6%) of the CRC tissues. High Sam68 expression correlated significantly with poor differentiation (P = 0.033), advanced T stage (P < 0.001), N stage (P = 0.023) and distant metastasis (P = 0.033). Sam68 nuclear localization correlated significantly with poor differentiation (P = 0.002) and T stage (P =0.021). Patients with high Sam68 expression or Sam68 nuclear localization had poorer overall survival than patients with low Sam68 expression or Sam68 cytoplasmic localization. Patients with high Sam68 expression had a higher risk of recurrence than those with low Sam68 expression. Conclusions: Overexpression of Sam68 correlated highly with cancer progression and poor differentiation in CRC. High Sam68 expression and Sam68 nuclear localization were associated with poorer overall survival. [ABSTRACT FROM AUTHOR]

Retraction note to: BMC Gastroenterol 2013, 13:126 https://doi.org/10.1186/1471-230X-13-126 The Editor has retracted this article after a number of concerns were raised, including: Overlapping panels in Figures 2 and 3 Inaccurate description of Figure 2 parts A-C in the figure legend Lack of discussion of the difference between the behaviour of the cell line COLO205 compared with the other cell lines used Lack of methodological information relating to the 9 paired colorectal cancer tissue samples No description of normal cell lines used and inconsistencies in the descriptions of colorectal cell lines The Editor no longer has confidence in the results and conclusions presented. Jun-Ling Liu, Zheng-Gen Wang, Ling Shi, Ting-Ting Li, Xiao-Hui Zhao, Xiu-Ting Chen and Yan-Qing Ding have not responded to correspondence from the Editor about this retraction. [Extracted from the article]

Fission and fusion of mitochondrial tubules are the major processes regulating mitochondrial morphology. However, the physiological significance of mitochondrial shape change is poorly understood. Glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells requires mitochondrial ATP production which evokes Ca2+ influx through plasma membrane depolarization, triggering insulin vesicle exocytosis. Therefore, GSIS reflects mitochondrial function and can be used for evaluating functional changes associated with morphological alterations of mitochondria. Using the insulin-secreting cell line INS-1E, we found that glucose stimulation induced rapid mitochondrial shortening and recovery. Inhibition of mitochondrial fission through expression of the dominant-negative mutant DLP1-K38A eliminated this dynamic mitochondrial shape change and, importantly, blocked GSIS. We found that abolishing mitochondrial morphology change in glucose stimulation increased the mitochondrial inner membrane proton leak, and thus significantly diminished the mitochondrial ATP producing capacity in response to glucose stimulation. These results demonstrate that dynamic change of mitochondrial morphology is a previously unrecognized component for metabolism-secretion coupling of pancreatic β-cells by participating in efficient ATP production in response to elevated glucose levels. [ABSTRACT FROM AUTHOR]

Blast furnace operation with natural gas (NG) injection is one of the effective measures to save energy, reduce CO2 emission, and decrease environmental load for iron and steel industry. Numerical simulations on blast furnace operation with NG injection through tuyeres are performed in this paper by raceway mathematical model, multi-fluid blast furnace model, and exergy analytical model. With increasing NG injection volume, the simulation results are shown as follows: (1) the theoretical flame temperature and bosh gas volume can be constant by decreasing blast volume and increasing oxygen enrichment. (2) The utilization rate of CO enhances while that of H2 decreases. The proportion of H2 in indirect reduction tends to be increased, which accelerates the reduction of burdens. The pressure drop shows that the permeability of blast furnace gets better. The blast furnace productivity is increased from 2.07 to 3.08 t · m−3 · day−1. The silicon content in hot metal is decreased from 0.26% to 0.05%. When BF operation with 125.4 kg · tHM−1 NG injection, coke rate and carbon emission rate are decreased by 27.2% and 32.2%, respectively. (3) The thermodynamic perfection degree is increased from 88.40% to 90.50%, the exergy efficiency is decreased from 51.94% to 49.02% and the chemical exergy of top gas is increased from 4.69 to 6.22 GJ · tHM−1. It is important to strengthen the recycling of top gas. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Angelicae Dahurica (Hoffm.)Benth.& Hook.f.ex Franch.&Sav combined with Pueraria labota (Willd.)Ohwi has been widely used as herb-pairs in traditional Chinese medicine (TCM) for utilization of antipyretic analgesic and anti-inflammatory drugs, and modern pharmacological studies have shown that application compatibility of the two drugs has the effects of cardiovascular disease treatment. The previous study has proved that Radix Angelicae Dahuricae extract could enhance the intestinal absorption of puerarin in Pueraria. But the underlying compatibility mechanism of the two herbs remains unknown. In this study we tried to further evaluate the improvement of Radix Angelicae Dahuricae extract on the puerarin using the Caco-2 cell model and explore the transport properties of puerarin through the above research to discuss the possible effect mechanism of Radix Angelicae Dahuricae extract on the transport of puerarin and the underlying compatibility mechanism of the two herbs. Aim of study: The aim of this work was to study the transport properties of puerarin in Radix Pueraria across Caco-2 cell membrane and to explore how the Radix Angelicae Dahuricae extract affected the transport of puerarin using the well-characterized, human-based intestinal Caco-2 cell model as a platform. Materials and methods: The bidirectional transport, and the effects of time, drug concentration, pH, P-gp inhibitors (Verapamil, Cyclosporin A), MRP inhibitor (MK-571) and EDTA-Na2 (tight junction modulator) on the absorption of puerarin were observed. Then the influence of extract of Radix Angelicae Dahuricae on the transport of puerarin was studied. Drug concentration was measured by HPLC and the apparent permeability coefficients (Papp) and apparent permeability ratio (PDR) were calculated. Results and conclusions: The results showed that the transport (Papp) of puerarin in Caco-2 cell monolayer model had time and concentration dependence, and the transport showed saturation characteristics with the time and concentration of puerarin to a certain degree. The Papp of puerarin transported on Caco-2 cell monolayer model was significantly changed when the specified inhibitors of P-gp were added to the model and the PDR decreased from 1.74 to 0.43. The absorption of puerarin was improved when combined with Radix Angelicae Dahuricae. The intestinal absorption of puerarin is by passive diffusion as the dominating process and active transportation was mediated by P-gp and MRP transporter in Caco-2 cell monolayer model, and Radix Angelicae Dahuricae could enhance the intestinal absorption of puerarin. [Copyright &y& Elsevier]

Abstract: The primary goal of this study was to explore the influence of neuroticism and resilience on life satisfaction and investigate the mediating effects of positive and negative affect on this relationship. A total of 282 participants were administered a battery of questionnaires that assessed neuroticism, resilience, positive and negative affect, and life satisfaction. Results from path analyses (AMOS) revealed that positive affect partially mediated the association between neuroticism and life satisfaction. Furthermore, the association between resilience and life satisfaction was fully mediated by positive affect. These findings highlight the mediational role of positive rather than negative affect in the relationships between neuroticism, resilience and life satisfaction. Results elaborate on the earlier findings connecting neuroticism and resilience to life satisfaction. Limitations of the study are considered and implications of the results for promotion of individuals’ life satisfaction are discussed. [Copyright &y& Elsevier]

Horizon picking from sub-bottom profiler (SBP) images has great significance in marine shallow strata studies. However, the mainstream automatic picking methods cannot handle multiples well, and there is a need to set a group of parameters manually. Considering the constant increase in the amount of SBP data and the high efficiency of deep learning (DL), we proposed a physicals-combined DL method to pick the horizons from SBP images. We adopted the DeeplabV3+ net to extract the horizons and multiples from SBP images. We generated a training dataset from the Jiaozhou Bay survey (Shandong, China) and the Zhujiang estuary survey (Guangzhou, China) to increase the applicability of the trained model. After the DL processing, we proposed a simulated Radon transform method to eliminate the surface-related multiples from the prediction by combining the designed pseudo-Radon transform and correlation analysis. We verified the proposed method using actual data (not involved in the training dataset) from Jiaozhou Bay and Zhujiang estuary. The positions of picked horizons are accurate, and multiples are suppressed. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor (VEGF) is a potent mediator of angiogenesis and vascular permeability, in which c-Src tyrosine kinase plays an essential role. However, the mechanisms by which VEGF stimulates c-Src activation have remained unclear. Here, we demonstrate that vascular endothelial cadherin (VE-cadherin) plays a critical role in regulating c-Src activation in response to VEGF. In vascular endothelial cells, VE-cadherin was basally associated with c-Src and Csk (C-terminal Src kinase), a negative regulator of Src activation. VEGF stimulated Csk release from VE-cadherin by recruiting the protein tyrosine phosphatase SHP2 to VE-cadherin signaling complex, leading to an increase in c-Src activation. Silencing VE-cadherin with small interference RNA significantly reduced VEGF-stimulated c-Src activation. Disrupting the association of VE-cadherin and Csk through the reconstitution of Csk binding-defective mutant of VE-cadherin also diminished Src activation. Moreover, inhibiting SHP2 by small interference RNA and adenovirus-mediated expression of a catalytically inactive mutant of SHP2 attenuated c-Src activation by blocking the disassociation of Csk from VE-cadherin. Furthermore, VE-cadherin and SHP2 differentially regulates VEGF downstream signaling. The inhibition of c-Src, VE-cadherin, and SHP2 diminished VEGF-mediated activation of Akt and endothelial nitric-oxide synthase. In contrast, inhibiting VE-cadherin and SHP2 enhanced ERK1/2 activation in response to VEGF. These findings reveal a novel role for VE-cadherin in modulating c-Src activation in VEGF signaling, thus providing new insights into the importance of VE-cadherin in VEGF signaling and vascular function. [ABSTRACT FROM AUTHOR]

Abstract: A reversing differential pulse voltammetry (RDPV) with a pre-accumulation step has been developed for simultaneous determination of quercetin and rutin in a mixture. A multi-wall carbon-nanotube paste electrode (CNTPE) was used for this purpose. Quercetin presented two oxidation steps at E m of 0.155 and E pa of 0.360V versus SCE, and rutin presented only one oxidation step at E m of 0.316V at the CNTPE. Strong adsorption and favorable assembly process of these species were observed on the electrode surface, based on which these species could be significantly pre-accumulated at the electrode for determination, resulting in considerably increased signals with well separated voltammetric peaks, allowing simultaneous detection. RDPV technique was used to select the first anodic peak of quercetin and the re-reduction peak of rutin for the determination, avoiding the peak overlap interferences. The electrochemical system was optimized for the selection of a suitable buffer system and pre-accumulation parameters such as adsorption potential and time duration. Finally, the multi-wall CNT paste electrode, as an electrochemical sensor, gave detecting sensitivities as high as 4.90μA/(μM quercetin) in the linear range of 0.05–5μM (in the presence of 10μM rutin) and 2.43μA/(μM rutin) in the linear range of 0.1–10μM (in the presence of 10μM quercetin). The applicability of the method to real sample analysis was also evaluated. [Copyright &y& Elsevier]

Acorus tatarinowii is a traditional aromatic resuscitation drug that can be clinically used to prevent cardiovascular diseases. The volatile oil of Acorus tatarinowii (VOA) possesses important medicinal properties, including protection against acute myocardial ischemia (MI) injury. However, the pharmacodynamic material basis and molecular mechanisms underlying this protective effect remain unclear. Using network pharmacology and animal experiments, we studied the mechanisms and pathways implicated in the activity of VOA against acute MI injury. First, VOA was extracted from three batches of Acorus tatarinowii using steam distillation, and then, its chemical composition was determined by GC-MS. Next, the components-targets and protein-protein interaction networks were constructed using systematic network pharmacology. Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were also conducted in order to predict the possible pharmacodynamic mechanisms. Furthermore, animal experiments including ELISAs, histological examinations, and Western blots were performed in order to validate the pharmacological effects of VOA. In total, 33 chemical components were identified in VOA, and ß-asarone was found to be the most abundant component. Based on network pharmacology analysis, the therapeutic effects of VOA against myocardial ischemia might be mediated by signaling pathways involving COX-2, PPAR-α, VEGF, and cAMP. Overall, the obtained results indicate that VOA alleviates the pathological manifestations of isoproterenol-hydrochloride-induced myocardial ischemia in rats, including the decreased SOD (superoxide dismutase) content and increased LDH (lactic dehydrogenase) content. Moreover, the anti-MI effect of VOA might be attributed to the downregulation of the COX-2 protein that inhibits apoptosis, the upregulation of the PPAR-α protein that regulates energy metabolism, and the activation of VEGF and cAMP signaling pathways. [ABSTRACT FROM AUTHOR]

Objectives: The current study was focused on preparing curcumin (CUR) supersaturated selfnano-emulsion (PI-CUR-SNEDDS) using hydrophilic polymer and to study the influence of polymer precipitation inhibitor on the physicochemical and biopharmaceutical properties of the PI-CUR-SNEDDS. Methods: PI-CUR-SNEDDS were prepared using hydrophilic polymer in order to maintain the supersaturation of CUR in nano-emulsion solution, artificial gastrointestinal fluid (AGF), and the precipitates formed, and characterised by in vitro dispersion tests, in vitro intestinal absorption and in vivo pharmacokinetic and compared with CUR-SNEDDS. Key findings: PI-CUR-SNEDDS prepared with 2% hydroxypropyl methylcellulose 55-60 (HPMC55-60) as precipitation inhibitor (PI) significantly improved the viscosity, physical stability and CUR's equilibrium solubility of nanoemulsion. HPMC55-60 and CUR interact in AGF through intermolecular interactions, form hydrogen bonds, and produce amorphous precipitates. Compared with CUR-SNEDDS, the proportion of CUR in the hydrophilic phase increased by about 3-fold, and apparent permeability coefficient (Papp) in duodenum, jejunum, ileum, and colon increased by 2.30, 3.65, 1.54 and 2.08-fold, respectively, and the area under the plasma concentration-time curve0-12h of PI-CUR-SNEDDS also increased by 3.50-fold. Conclusions: Our results suggested that HPMC55-60 maintained the CUR supersaturation state by forming hydrogen bonds with CUR, increasing the solution's viscosity and drug solubilisation, thus improving the absorption and bioavailability of CUR. [ABSTRACT FROM AUTHOR]

Angiogenesis, the formation of new blood vessels, is tightly regulated by gene transcriptional programs. Yin Ying 1 (YY1) is a ubiquitously distributed transcription factor with diverse and complex biological functions; however, little is known about the cell-type-specific role of YY1 in vascular development and angiogenesis. Here we report that endothelial cell (EC)-specific YY1 deletion in mice led to embryonic lethality as a result of abnormal angiogenesis and vascular defects. Tamoxifen-inducible EC-specific YY1 knockout (YY1iΔEC) mice exhibited a scarcity of retinal sprouting angiogenesis with fewer endothelial tip cells. YY1iΔEC mice also displayed severe impairment of retinal vessel maturation. In an ex vivo mouse aortic ring assay and a human EC culture system, YY1 depletion impaired endothelial sprouting and migration. Mechanistically, YY1 functions as a repressor protein of Notch signaling that controls EC tip-stalk fate determination. YY1 deficiency enhanced Notch-dependent gene expression and reduced tip cell formation. Specifically, YY1 bound to the N-terminal domain of RBPJ (recombination signal binding protein for Ig Kappa J region) and competed with the Notch coactivator MAML1 (mastermind-like protein 1) for binding to RBPJ, thereby impairing the NICD (intracellular domain of the Notch protein)/MAML1/RBPJ complex formation. Our study reveals an essential role of endothelial YY1 in controlling sprouting angiogenesis through directly interacting with RBPJ and forming a YY1-RBPJ nuclear repression complex. [ABSTRACT FROM AUTHOR]

Serum response factor (SRF), a key transcription factor, plays an important role in regulating cell functions such as proliferation and differentiation. Most proteins are unstable, and protein stability is regulated through the ubiquitin-proteasome system (UPS) or the autophagy lysosome pathway (ALP). Whether SRF is degraded and what mechanisms control SRF protein stability remain unexplored. Western blot analyses of cells treated with cycloheximide (CHX), a protein synthesis inhibitor, showed that SRF was degraded in a time-dependent manner. Moreover, we observed that SRF undergoes autophagy-dependent destruction, which is accelerated by serum deprivation. Through bioinformatics screening, we found that SRF contains the GSK3β phosphorylation motif (T/SPPXS): SPDSPPRSDPT, which is conserved from zebrafish to humans. Serum deprivation stimulated GSK3β activation that then potentiates SRF degradation through the autophagy lysosome pathway. Since SRF is important for numerous cellular activities, our results suggest that the autophagy-dependent SRF degradation pathway may provide a new avenue to modulate SRF-mediated cell functions. • SRF undergoes degradation through the autophagy lysosome pathway but not the ubiquitin-proteasome system. • SRF's degradation is accelerated by serum deprivation. • Serum deprivation-stimulated GSK3β activation promotes the degradation of SRF. [ABSTRACT FROM AUTHOR]

Liver fibrosis is a common consequence of various chronic hepatitis and liver injuries. The myofibroblasts, through the accumulation of extracellular matrix (ECM) proteins, are closely associated with the progression of liver fibrosis. However, the molecular mechanisms underlying transcriptional regulation of fibrogenic genes and ECM proteins in myofibroblasts remain largely unknown. Using tamoxifen inducible myofibroblast-specific Cre-expressing mouse lines with selective deletion of the transcription factor Yin Yang 1 (YY1), here we show that YY1 deletion in myofibroblasts mitigates carbon tetrachloride-induced liver fibrosis. This protective effect of YY1 ablation on liver fibrosis was accompanied with reduced expression of profibrogenic genes and ECM proteins, including TNF-α, TGF-β, PDGF, IL-6, α-SMA and Col1α1 in liver tissues from YY1 mutant mice. Moreover, using the human hepatic stellate cell (HSC) line LX-2, we found that knockdown of YY1 in myofibroblasts by siRNA treatment diminished myofibroblast proliferation, α-SMA expression, and collagen deposition. Collectively, our findings reveal a specific role of YY1 in hepatic myofibroblasts and suggest a new therapeutic strategy for hepatic fibrosis-associated liver diseases. • Myofibroblast-specific deletion of YY1 in mice attenuated carbon tetrachloride-induced liver fibrosis. • YY1 deficiency in myofibroblasts in vivo inhibited expression of profibrogenic genes including TGF-β and PDGF, α-SMA and collagens. • YY1 depletion in human hepatic stellate cells diminished profibrogenic property of myofibroblasts under TGF-b stimulation. [ABSTRACT FROM AUTHOR]

Atherosclerosis is the primary underlying cause of cardiovascular disease which preferentially develops at arterial regions exposed to disturbed flow (DF), but much less at regions of unidirectional laminar flow (UF). Recent studies have demonstrated that DF and UF differentially regulate important aspects of endothelial function, such as vascular inflammation, oxidative stress, vascular tone, cell proliferation, senescence, mitochondrial function, and glucose metabolism. DF and UF regulate vascular pathophysiology via differential regulation of mechanosensitive transcription factors (MSTFs) (KLF2, KLF4, NRF2, YAP/TAZ/TEAD, HIF-1α, NF-κB, AP-1, and others). Emerging studies show that MSTFs represent promising therapeutic targets for the prevention and treatment of atherosclerosis. We present here a comprehensive overview of the role of MSTFs in atherosclerosis, and highlight future directions for developing novel therapeutic agents by targeting MSTFs. Highlights UF and DF differentially modulate several MSTFs in endothelial cells. MSTFs regulate multiple aspects of endothelial function, including inflammation, proliferation, thrombosis, oxidative stress, and endothelial cell metabolism. MSTFs crosstalk with each other and functionally regulate endothelial gene expression and function. Targeting MSTFs could be a promising therapeutic strategy for atherosclerosis. [ABSTRACT FROM AUTHOR]

Abstract Atherosclerosis, the principal cause of cardiovascular death worldwide, is a pathological disease characterized by fibro-proliferation, chronic inflammation, lipid accumulation, and immune disorder in the vessel wall. As the atheromatous plaques develop into advanced stage, the vulnerable plaques are prone to rupture, which causes acute cardiovascular events, including ischemic stroke and myocardial infarction. Emerging evidence has suggested that atherosclerosis is also an epigenetic disease with the interplay of multiple epigenetic mechanisms. The epigenetic basis of atherosclerosis has transformed our knowledge of epigenetics from an important biological phenomenon to a burgeoning field in cardiovascular research. Here, we provide a systematic and up-to-date overview of the current knowledge of three distinct but interrelated epigenetic processes (including DNA methylation, histone methylation/acetylation, and non-coding RNAs), in atherosclerotic plaque development and instability. Mechanistic and conceptual advances in understanding the biological roles of various epigenetic modifiers in regulating gene expression and functions of endothelial cells (vascular homeostasis, leukocyte adhesion, endothelial-mesenchymal transition, angiogenesis, and mechanotransduction), smooth muscle cells (proliferation, migration, inflammation, hypertrophy, and phenotypic switch), and macrophages (differentiation, inflammation, foam cell formation, and polarization) are discussed. The inherently dynamic nature and reversibility of epigenetic regulation, enables the possibility of epigenetic therapy by targeting epigenetic "writers", "readers", and "erasers". Several Food Drug Administration-approved small-molecule epigenetic drugs show promise in pre-clinical studies for the treatment of atherosclerosis. Finally, we discuss potential therapeutic implications and challenges for future research involving cardiovascular epigenetics, with an aim to provide a translational perspective for identifying novel biomarkers of atherosclerosis, and transforming precision cardiovascular research and disease therapy in modern era of epigenetics. [ABSTRACT FROM AUTHOR]

SENCR is a human-specific, vascular cell-enriched long-noncoding RNA (lncRNA) that regulates vascular smooth muscle cell and endothelial cell (EC) phenotypes. The underlying mechanisms of action of SENCR in these and other cell types is unknown. Here, levels of SENCR RNA are shown to be elevated in several differentiated human EC lineages subjected to laminar shear stress. Increases in SENCR RNA are also observed in the laminar shear stress region of the adult aorta of humanized SENCR-expressing mice, but not in disturbed shear stress regions. SENCR loss-of-function studies disclose perturbations in EC membrane integrity resulting in increased EC permeability. Biotinylated RNA pull-down and mass spectrometry establish an abundant SENCR-binding protein, cytoskeletal-associated protein 4 (CKAP4); this ribonucleoprotein complex was further confirmed in an RNA immunoprecipitation experiment using an antibody to CKAP4. Structure-function studies demonstrate a noncanonical RNA-binding domain in CKAP4 that binds SENCR. Upon SENCR knockdown, increasing levels of CKAP4 protein are detected in the EC surface fraction. Furthermore, an interaction between CKAP4 and CDH5 is enhanced in SENCR-depleted EC. This heightened association appears to destabilize the CDH5/CTNND1 complex and augment CDH5 internalization, resulting in impaired adherens junctions. These findings support SENCR as a flow-responsive lncRNA that promotes EC adherens junction integrity through physical association with CKAP4, thereby stabilizing cell membrane-bound CDH5. [ABSTRACT FROM AUTHOR]

Late embryogenesis abundant (LEA) proteins are closely related to abiotic stress tolerance of plants. In the present study, we identified a novel Em-like gene from lettuce, termed LsEm1, which could be classified into group 1 LEA proteins, and shared high homology with Cynara cardunculus Em protein. The LsEm1 protein contained three different 20-mer conserved elements (C-element, N-element, and M-element) in the C-termini, N-termini, and middle-region, respectively. The LsEm1 mRNAs were accumulated in all examined tissues during the flowering and mature stages, with a little accumulation in the roots and leaves during the seedling stage. Furthermore, the LsEm1 gene was also expressed in response to salt, dehydration, abscisic acid (ABA), and cold stresses in young seedlings. The LsEm1 protein could effectively reduce damage to the lactate dehydrogenase (LDH) and protect LDH activity under desiccation and salt treatments. The Escherichia coli cells overexpressing the LsEm1 gene showed a growth advantage over the control under drought and salt stresses. Moreover, LsEm1-overexpressing rice seeds were relatively sensitive to exogenously applied ABA, suggesting that the LsEm1 gene might depend on an ABA signaling pathway in response to environmental stresses. The transgenic rice plants overexpressing the LsEm1 gene showed higher tolerance to drought and salt stresses than did wild-type (WT) plants on the basis of the germination performances, higher survival rates, higher chlorophyll content, more accumulation of soluble sugar, lower relative electrolyte leakage, and higher superoxide dismutase activity under stress conditions. The LsEm1-overexpressing rice lines also showed less yield loss compared with WT rice under stress conditions. Furthermore, the LsEm1 gene had a positive effect on the expression of the OsCDPK9, OsCDPK13, OsCDPK15, OsCDPK25, and rab21 (rab16a) genes in transgenic rice under drought and salt stress conditions, implying that overexpression of these genes may be involved in the enhanced drought and salt tolerance of transgenic rice. Thus, this work paves the way for improvement in tolerance of crops by genetic engineering breeding. [ABSTRACT FROM AUTHOR]

MicroRNA miR-126 has been shown to be required for proper angiogenesis in several models. However, its expression, regulation and function in the mouse choroid remain unclear. Our previous data has shown that miR-126 expression is enriched in the endothelial cells (ECs) of the mouse choroid. Here we report that a 5.5 kb Egfl7/miR-126 promoter drives the expression of miR-126 in the choroid ECs during choroidal vascular development. The expression of miR-126 in the ECs is regulated by flow stress likely through Krüppel-like transcriptional factors. miR-126 −/− mice show mildly delayed choroidal vascular development, but adult knockout mice develop periphery choroidal vascular lesions. This study suggests that miR-126 is largely dispensable for mouse choroidal development but required for maintaining choroidal vasculature integrity. [ABSTRACT FROM AUTHOR]

Sirtuin 1 (SIRT1) is an NAD + -dependent protein deacetylase that plays a critical role in controlling energy metabolism, stress response and aging. Hence, enhancing SIRT1 activity could be a potential therapeutic strategy to treat metabolic diseases such as diabetes. However, pharmacological activators for SIRT1 are scarce to date. In this study, using the optimized high throughput screening, we identified E6155, a piperazine 1, 4- diamide compound, as a new small molecular activator of SIRT1. We further found that E6155 significantly upregulated glucose uptake in cultured normal liver cells and skeletal muscle cells through increasing SIRT1 deacetylase activity. In type 2 diabetic KKA y mice, E6155 treatment markedly decreased the level of fasting glucose. Moreover, E6155 improved oral glucose tolerance and insulin tolerance. Euglycemic clamp and the homeostasis model assessment of insulin resistance index showed that E6155 ameliorated the insulin resistance and increased insulin sensitivity in diabetic mice. Mechanistically, we observed that the antidiabetic effects of E6155 were involved in SIRT1 dependent activation of LKB1/AMPK and IRS1/AKT pathways. In conclusion, our findings identified E6155 as a novel SIRT1 activator and suggested that E6155 could be a promising drug candidate for treating insulin resistance and diabetes. [ABSTRACT FROM AUTHOR]