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[Display omitted] • Two polysaccharides were obtained from unprocessed and Lactobacillus fermented litchi pulp (named LP and LPF, respectively). • LPF was more readily utilized by bacteria than LP. • LPF enhanced the levels of short-chain fatty acids than LP. • LPF increased the growth of Bifidobacterium , Prevotella , and Bacteroides than LP. • Structure-prebiotic activity relationship of litchi polysaccharides was elaborated. In this study, litchi polysaccharides were obtained from unfermented or fermented pulp by Lactobacillus fermentum (denoted as LP and LPF, respectively). The differences between LP and LPF in the colonic fermentation characteristics and modulatory of gut microbiota growth and metabolism were investigated with an in vitro fecal fermentation model. Results revealed that the strategies of gut bacteria metabolizing LP and LPF were different and LPF with lower molecular weight (Mw) was readily utilized by bacteria. The monosaccharide utilization sequence of each polysaccharide was Ara > Gla > GalA > GlcA ≈ Glu ≈ Man. Moreover, LPF promoted stronger proliferation of Bifidobacterium , Megamonas , Prevotella , and Bacteroides and higher SCFAs production (especially acetic and butyric acids) than LP. Correlation analysis further revealed that Mw could represent an essential structural feature of polysaccharides associated with its microbiota-regulating effect. Overall, Lactobacillus fermentation pre-treatment of litchi pulp promoted the fermentation characteristics and prebiotic activities of its polysaccharide. [ABSTRACT FROM AUTHOR]

Aims The present study aims to investigate the role of Akt in the regulation of urinary bladder organ hypertrophy caused by partial bladder outlet obstruction (pBOO). Main methods Male rats were surgically induced for pBOO. Real-time PCR and western blot were used to examine the levels of mRNA and protein. A phosphoinositide 3-kinase (PI3K) inhibitor LY294002 was used to inhibit the activity of endogenous Akt. Key findings The urinary bladder developed hypertrophy at 2 weeks of pBOO. The protein but not mRNA levels of type I collagen and α-smooth muscle actin (αSMA) were increased in pBOO bladder when compared to sham control. The phosphorylation (activation) levels of Akt1 (p-Ser 473 ), mammalian target of rapamycin (mTOR), p70S6 kinase (p70S6K), and 4E-BP1 were also increased in pBOO bladder. LY294002 treatment reduced the phosphorylation levels of Akt1 and 4E-BP1, and the protein levels of type I collagen and αSMA in pBOO bladder. The mRNA and protein levels of proliferating cell nuclear antigen (PCNA) were increased in pBOO bladder, and PCNA up-regulation occurred in urothelial not muscular layer. LY294002 treatment had no effect on the mRNA and protein levels of PCNA in pBOO bladder. LY294002 treatment partially reduced the bladder weight caused by pBOO. Significance pBOO-induced urinary bladder hypertrophy is attributable to fibrosis, smooth muscle cellular hypertrophy, and urothelium cell hyper-proliferation. Akt1-mediated protein synthesis in pBOO bladder contributes to type I collagen and αSMA but not PCNA up-regulation. Target of Akt1 is necessary but not sufficient in treatment of urinary bladder hypertrophy following pBOO. [ABSTRACT FROM AUTHOR]

Patients with inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS) often experience increased sensory responsiveness in the urinary bladder reflecting neurogenic bladder overactivity. Here we demonstrate that colitis-induced up-regulation of the phospholipase C gamma (PLCγ) pathway downstream of brain-derived neurotrophic factor (BDNF) in bladder afferent neurons in the dorsal root ganglia (DRG) plays essential roles in activating these neurons thereby leading to bladder hyperactivity. Upon induction of colitis with 2,4,6-trinitrobenzenesulfonic acid (TNBS) in rats, we found that the phosphorylation (activation) level of cAMP responsive element-binding (p-CREB) protein, a molecular switch of neuronal plasticity, was increased in specifically labeled bladder afferent neurons in the thoracolumbar and lumbosacral DRGs. In rats having reduced levels of BDNF (BDNF +/− ), colitis failed to elevate CREB protein activity in bladder afferent neurons. Physiological examination also demonstrated that colitis-induced urinary frequency was not shown in BDNF +/− rats, implicating an essential role of BDNF in mediating colon-to-bladder sensory cross-sensitization. We further implemented in vivo and in vitro studies and demonstrated that BDNF-mediated colon-to-bladder sensory cross-activation involved the TrkB–PLCγ–calcium/calmodulin-dependent protein kinase II (CaMKII) cascade. In contrast, the PI3K/Akt pathway was not activated in bladder afferent neurons during colitis and was not involved in BDNF action in the DRG. Our results suggest that colon-to-bladder sensory cross-sensitization is regulated by specific signal transduction initiated by the up-regulation of BDNF in the DRG. [ABSTRACT FROM AUTHOR]

Real time myocardial contrast echocardiography (RTMCE) is a cost-effective and simple method to quantify coronary flow reserve ( CFR). We aimed to determine the value of RTMCE to predict cardiac events after percutaneous coronary intervention ( PCI). We have studied myocardial blood volume (A), velocity ( β), flow indexes ( MBF, A × β), and vasodilator reserve (stress-to-rest ratios) in 36 patients with acute coronary syndrome ( ACS) who underwent PCI. CFR ( MBF at stress/ MBF at rest) was calculated for each patient. Perfusion scores were used for visual interpretation by MCE and correlation with TIMI flow grade. In qualitative RTMCE assessment, post- PCI visual perfusion scores were higher than pre- PCI (Z = −7.26, P < 0.01). Among 271 arteries with TIMI flow grade 3 post- PCI, 72 (36%) did not reach visual perfusion score 1. The β- and A × β-reserve of the abnormal segments supplied by obstructed arteries increased after PCI comparing to pre- PCI values (P < 0.01). Patients with adverse cardiac events had significantly lower β- and lower A × β-reserve than patients without adverse cardiac events. In the former group, the CFR was ≥ 1.5 both pre- and post- PCI. CFR estimation by RTMCE can quantify myocardial perfusion in patients with ACS who underwent PCI. The parameters β-reserve and CFR combined might predict cardiac events on the follow-up. [ABSTRACT FROM AUTHOR]

In the device-to-device (D2D) underlaying LTE-Advanced (LTE-A) systems, unlike the existing works which formulate the resources sharing problem as a disjoint coalition formation game, in this letter we propose a novel overlapping coalition formation game (OCFG) based scheme to coordinate the interference between these two subsystems. By sharing uplink spectrums, in this game each D2D pair is allowed to join multiple coalitions simultaneously to improve the spectral efficiency and maximize the system utility. The merge-and-split rule is designed to adapt to the dynamic environment and a discrete-time Markov chain based analysis is utilized to present the stability. Compared with traditional methods, simulations demonstrate the significant performance enhancement of the proposed algorithm in terms of the complexity and D2D system sum throughput. [ABSTRACT FROM AUTHOR]

This study utilized magnetic resonance imaging (MRI) to monitor the real-time status of the urinary bladder in normal and diseased states following cyclophosphamide (CYP)-induced cystitis, and also examined the role of the phosphoinositide 3-kinase (PI3K) pathway in the regulation of urinary bladder hypertrophy in vivo. Our results showed that under MRI visualization the urinary bladder wall was significantly thickened at 8 h and 48 h post CYP injection. The intravesical volume of the urinary bladder was also markedly reduced. Treatment of the cystitis animals with a specific PI3K inhibitor LY294002 reduced cystitis-induced bladder wall thickening and enlarged the intravesical volumes. To confirm the MRI results, we performed H&E stain postmortem and examined the levels of type I collagen by real-time PCR and western blot. Inhibition of the PI3K in vivo reduced the levels of type I collagen mRNA and protein in the urinary bladder ultimately attenuating cystitis-induced bladder hypertrophy. The bladder mass calculated according to MRI data was consistent to the bladder weight measured ex vivo under each drug treatment. MRI results also showed that the urinary bladder from animals with cystitis demonstrated high magnetic signal intensity indicating considerable inflammation of the urinary bladder when compared to normal animals. This was confirmed by examination of the pro-inflammatory factors showing that interleukin (IL)-1α, IL-6 and tumor necrosis factor (TNF)α levels in the urinary bladder were increased with cystitis. Our results suggest that MRI can be a useful technique in tracing bladder anatomy and examining bladder hypertrophy in vivo during disease development and the PI3K pathway has a critical role in regulating bladder hypertrophy during cystitis. [ABSTRACT FROM AUTHOR]

Based on the previous work in our group and the principle of computer-aided drug design, a series of novel β-amino pyrrole-2-carbonitrile derivatives was designed and synthesized. Compounds 8l and 9l were efficacious and selective DPP4 inhibitors resulting in decreased blood glucose in vivo . Compound 8l had moderate DPP4 inhibitory activity (IC 50 = 0.05 μM) and good oral bioavailability ( F = 53.2%). Compound 9l showed excellent DPP4 inhibitory activity (IC 50 = 0.01 μM), good selectivity (selective ratio: DPP8/DPP4 = 898.00; DPP9/DPP4 = 566.00) against related peptidases, and good efficacy in an oral glucose tolerance tests in ICR mice and moderate PK profiles ( F = 22.8%, t 1/2 = 2.74 h). Moreover, compound 9l did not block hERG channel and exhibited no inhibition of liver metabolic enzymes such as CYP2C9. [ABSTRACT FROM AUTHOR]

Hypocretin/orexin-producing neurons, located in the perifornical region of the lateral hypothalamus area (LHA) and projecting to the brain sites of rostral ventrolateral medulla (RVLM), involve in the increase of sympathetic activity, thereby regulating cardiovascular function. The current study was designed to test the hypothesis that the central orexin-A (OXA) could be involved in the cardiovascular dysfunction of acute myocardial infarction (AMI) by releasing NAD(P)H oxidase-derived superoxide anion (O2−) generation in RVLM, AMI rat model established by ligating the left anterior descending (LAD) coronary artery to induce manifestation of cardiac dysfunction, monitored by the indicators as heart rate (HR), heart rate variability (HRV), mean arterial pressure (MAP) and left intraventricular pressure. The results showed that the expressions of OXA in LHA and orexin 1 receptor (OX1R) increased in RVLM of AMI rats. The double immunofluorescent staining indicated that OX1R positive cells and NAD(P)H oxidative subunit gp91phox or p47phox-immunoreactive (IR) cells were co-localized in RVLM. Microinjection of OXA into the cerebral ventricle significantly increased O2− production and mRNA expression of NAD(P)H oxidase subunits when compared with aCSF-treated ones. Exogenous OXA administration in RVLM produced pressor and tachycardiac effects. Furthermore, the antagonist of OX1R and OX2R (SB-408124 and TCS OX2 29, respectively) or apocynin (APO), an inhibitor of NAD(P)H oxidase, partly abolished those cardiovascular responses of OXA. HRV power spectral analysis showed that exogenous OXA led to decreased HF component of HRV and increased LF/HF ratio in comparison with aCSF, which suggested that OXA might be related to sympathovagal imbalance. As indicated by the results, OXA might participate in the central regulation of cardiovascular activities by disturbing the sympathovagal balance in AMI, which could be explained by the possibility that OXR and NAD(P)H-derived O2− in RVLM mediates OXA-induced cardiovascular responses. [ABSTRACT FROM AUTHOR]

Abstract: The goal of this study was to investigate the effects of antioxidant supplementation on the quality of flow cytometrically-sorted boar spermatozoa. The effects of ascorbic acid-2-glucoside (AA-2G) on the sex-sorting process were evaluated using a variety of concentrations. The effects of different antioxidants (AA-2G, l-glutathione, and vitamin E) on the viability and lifespan of boar spermatozoa were also compared during sorting. Furthermore, the effect of AA-2G on acrosome intactness, the capacitation ability of sorted boar spermatozoa and pregnancy efficiency after artificial insemination (AI) at different sorting-to-insemination intervals were examined. Greater (P <0.05) percentages of motile spermatozoa and acrosome intactness and longer storage time periods were observed in the AA-2G-supplemented group when compared with the other antioxidant-supplemented or control groups. At an AA-2G concentration of 0.068mg/mL, the motility characteristics (i.e., straightness (STR), velocity according to the average path (VAP), and amplitude of the sperm head lateral displacement (ALH)) of the sex-sorted boar spermatozoa were greater (P <0.05) than in those treated with other AA-2G concentrations. The capacitation rate of boar spermatozoa in the AA-2G-supplemented group was less (P <0.05) than that in the control group. After sorting-to-insemination interval of 10h, the pregnancy rates after AI with boar spermatozoa for the AA-2G-supplemented group were 59.25%, while the control group remains no sufficient quality semen. This study demonstrates that AA-2G supplementation can improve the quality of flow cytometrically sorted boar spermatozoa and that the optimal concentration of AA-2G for sorting is 0.068mg/mL. [Copyright &y& Elsevier]

Abstract: The combustion assisted thermal spray systems are being used to apply coatings to prevent surface degradation. They offer a highly attractive way to modify the surface properties of the substrate to extend the product life. In addition to the materials being sprayed, the quality of combustion assisted thermal spray coating depends greatly on the flow behavior of reacting gases and particle dynamics. The present study investigates the effect of gas phase and its interaction with particles through the nozzle of a thermal spray gun by developing a comprehensive mathematical model. The objective is to develop a predictive understanding of various design parameters of combustion assisted thermal spray systems. The model was developed by considering the conservation of mass, momentum and energy of reacting gases. The particle dynamics was decoupled from the gas phase dynamics since the particle loading in the spray process is very low. The developed model was employed to investigate the influence of various design parameters on the coating quality of thermal spray process. [Copyright &y& Elsevier]

Background: Langerhans cell histiocytosis is a rare disease that occurs mainly in children, and hepatic involvement is generally a poor prognostic factor.Objective: To describe CT and MRI findings of hepatic involvement of Langerhans cell histiocytosis in children, especially the abnormal bile duct manifestation on magnetic resonance cholangiopancreatography (MRCP).Materials and Methods: Thirteen children (seven boys, six girls; mean age 28.9 months) were diagnosed with disseminated Langerhans cell histiocytosis. They underwent CT (n = 5) or MRI (n = 4), or CT and MRI examinations (n = 4) to evaluate the liver involvement.Results: Periportal abnormalities presented as band-like or nodular lesions on CT and MRI in all 13 children. The hepatic parenchymal lesions were found in the peripheral regions of the liver in seven children, including multiple nodules on MRI (n = 6), and cystic-like lesions on CT and MRI (n = 3). In 11 of the 13 children the dilatations of the bile ducts were observed on CT and MRI. Eight of the 13 children underwent MR cholangiopancreatography, which demonstrated stenoses or segmental stenoses with slight dilatation of the central bile ducts, including the common hepatic duct and its first-order branches. The peripheral bile ducts in these children showed segmental dilatations and stenoses.Conclusion: Stenosis of the central bile ducts revealed by MR cholangiopancreatography was the most significant finding of liver involvement in Langerhans cell histiocytosis in children. [ABSTRACT FROM AUTHOR]

Background: Langerhans cell histiocytosis is a rare disease that occurs mainly in children, and hepatic involvement is generally a poor prognostic factor. Objective: To describe CT and MRI findings of hepatic involvement of Langerhans cell histiocytosis in children, especially the abnormal bile duct manifestation on magnetic resonance cholangiopancreatography (MRCP). Materials and methods: Thirteen children (seven boys, six girls; mean age 28.9 months) were diagnosed with disseminated Langerhans cell histiocytosis. They underwent CT ( n = 5) or MRI ( n = 4), or CT and MRI examinations ( n = 4) to evaluate the liver involvement. Results: Periportal abnormalities presented as band-like or nodular lesions on CT and MRI in all 13 children. The hepatic parenchymal lesions were found in the peripheral regions of the liver in seven children, including multiple nodules on MRI ( n = 6), and cystic-like lesions on CT and MRI ( n = 3). In 11 of the 13 children the dilatations of the bile ducts were observed on CT and MRI. Eight of the 13 children underwent MR cholangiopancreatography, which demonstrated stenoses or segmental stenoses with slight dilatation of the central bile ducts, including the common hepatic duct and its first-order branches. The peripheral bile ducts in these children showed segmental dilatations and stenoses. Conclusion: Stenosis of the central bile ducts revealed by MR cholangiopancreatography was the most significant finding of liver involvement in Langerhans cell histiocytosis in children. [ABSTRACT FROM AUTHOR]

Background: Microglial mediated neuroinflammation in the rostral ventrolateral medulla (RVLM) plays roles in the etiology of stress-induced hypertension (SIH). It was reported that autophagy influenced inflammation via immunophenotypic switching of microglia. High-mobility group box 1 (HMGB1) acts as a regulator of autophagy and initiates the production of proinflammatory cytokines (PICs), but the underlying mechanisms remain unclear.Methods: The stressed mice were subjected to intermittent electric foot shocks plus noises administered for 2 h twice daily for 15 consecutive days. In mice, blood pressure (BP) and renal sympathetic nerve activity (RSNA) were monitored by noninvasive tail-cuff method and platinum-iridium electrodes placed respectively. Microinjection of siRNA-HMGB1 (siHMGB1) into the RVLM of mice to study the effect of HMGB1 on microglia M1 activation was done. mRFP-GFP-tandem fluorescent LC3 (tf-LC3) vectors were transfected into the RVLM to evaluate the process of autolysosome formation/autophagy flux. The expression of RAB7, lysosomal-associated membrane protein 1 (LAMP1), and lysosomal pH change were used to evaluate lysosomal function in microglia. Mitophagy was identified by transmission electron microscopic observation or by checking LC3 and MitoTracker colocalization under a confocal microscope.Results: We showed chronic stress increased cytoplasmic translocations of HMGB1 and upregulation of its receptor RAGE expression in microglia. The mitochondria injury, oxidative stress, and M1 polarization were attenuated in the RVLM of stressed Cre-CX3CR1/RAGEfl/fl mice. The HMGB1/RAGE axis increased at the early stage of stress-induced mitophagy flux while impairing the late stages of mitophagy flux in microglia, as revealed by decreased GFP fluorescence quenching of GFP-RFP-LC3-II puncta and decreased colocalization of lysosomes with mitochondria. The expressions of RAB7 and LAMP1 were decreased in the stressed microglia, while knockout of RAGE reversed these effects and caused an increase in acidity of lysosomes. siHMGB1 in the RVLM resulted in BP lowering and RSNA decreasing in SIH mice. When the autophagy inducer, rapamycin, is used to facilitate the mitophagy flux, this treatment results in attenuated NF-κB activation and reduced PIC release in exogenous disulfide HMGB1 (ds-HMGB1)-stimulated microglia.Conclusions: Collectively, we demonstrated that inhibition of the HMGB1/RAGE axis activation led to increased stress-induced mitophagy flux, hence reducing the activity of microglia-mediated neuroinflammation and consequently reduced the sympathetic vasoconstriction drive in the RVLM. [ABSTRACT FROM AUTHOR]

In this work, aiming at finding a novel, potent, and selective sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor with good pharmacokinetic profiles for the treatment of diabetes, we focus on modifying the sugar moiety of SGLT2 inhibitors, which dominates the binding with glucose binding site of hSGLT, via removing the C-6 hydroxy group to adjust the physicochemical properties and target-recognition manners of SGLT2 inhibitors. In addition, tofogliflozin containing a special O -spiroketal C -arylglucoside scaffold, displayed good efficacy and bioavailability both in animals and in humans. Therefore, a series of 6-deoxy O -spiroketal C -arylglucosides as novel SGLT2 inhibitors were designed, synthesized, and evaluated in this work. The structure-activity relationship (SAR) research on this novel series and a comprehensive in vitro and in vivo biological evaluation afforded compound 39 with high in vitro hSGLT2 inhibitory activity (IC 50 = 4.5 nM), good pharmacokinetic profiles, and more remarkable efficacy in C57BL/6J mice and Sprague-Dawley rats than marketed drug tofogliflozin. Image 1 • Novel 6-deoxy O -spiroketal C -arylglucosides as SGLT2 inhibitors were designed, synthesized, and evaluated. • The structure-activity relationship (SAR) of this novel series of 31 compounds was demonstrated. • Compound 39 demonstrated higher potency of inhibiting hSGLT2 than dapagliflozin (IC 50 = 4.5 nM vs 8.3 nM). • Compound 39 displayed greater efficacy than tofogliflozin on urinary glucose excretion and oral glucose tolerance in mice. • The half-life of compound 39 in mice was longer than tofogliflozin after oral administration (5.95 h vs 2.57 h). [ABSTRACT FROM AUTHOR]

Central neuroinflammation produced by both innate and adaptive immunities plays a major role in the development of stress-induced hypertension (SIH), but successful T cell immunoregulation for SIH requires that the T cells can access brain tissues. So far, both the effects of T helper 17 (Th17) cells on SIH and the pathway for T cells entry into the brain were unknown. Here we show that the blood pressure (BP), heart rate (HR) and the norepinephrine(NE) of the SIH rats were considerably higher, the numbers of Th17 cells and IL-17 were higher, relative to control. Anti-IL-17 attenuated the elevation of BP and HR of the SIH rats when microinjected into the paraventricular nucleus (PVN).Alb-FITC, after infusion into the carotid artery, were found in the brain parenchyma of the PVN in the SIH rats. We concluded that Th17 cells infiltrated the parenchyma of the paraventricular nucleus (PVN) via a compromised blood brain barrier (BBB) in response to stress and Th17 cells and IL-17 play an important role in the pathophysiology of SIH. • The permeability of BBB increased and Th17 cells infiltrate into brain parenchyma in the PVN of SIH rats. • ROR-γt or CD4 and IL-17 co-existin the paraventricular hypothalamic nucleus and expression of IL-17, CD4 or ROR-γt increased. • Microinjection of Anti-IL-17 in the PVN reduced the serum NE concentration and decreased systolic blood pressure of SIH rats. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that neuroinflammation and oxidative stress in cardiovascular center contribute to the pathological processes underlying hypertension. Microglia activation triggers the inflammation and oxidative stress. Melatonin is a documented potent anti-inflammatory regent and antioxidant, the underlying roles of melatonin in regulating microglia activation via mitochondria remain unclear. In present study, we investigated the protective role of melatonin in decreasing M1 phenotype switching via attenuating mitochondrial oxidative damage in dependence on uncoupling protein 2 (UCP2) pathway in microglia. Prorenin (20 nmol/L; 24 hr) was used to induce inflammation in cultured microglia. Mitochondrial morphology was detected by transmission electron microscope. The reactive oxygen species (ROS) production by using DCFH-DA fluorescence imaging and mitochondrial membrane potential (MMP, ΔΨm) was evaluated by JC-1 staining. The indicator of the redox status as the ratio of the amount of total NADP+ to total NADPH, and the expression of 6 subunits of NADPH oxidase is measured. The pro-inflammatory cytokines releasing was measured by qPCR. UCP2 and activated AMPKα (p-AMPKα) expression were examined by immunoblot. Melatonin (100 μM) markedly alleviated the M1 microglia phenotype shifting and abnormal mitochondria morphology. Melatonin attenuated prorenin-induced ΔΨm increasing and ROS overproduction. Melatonin decreased the redox ratio (NADP+/NADPH) and the p47phox and gp91phox subunits of NADPH oxidase expression in prorenin-treated microglia. These effects were reversed in the presence of UCP2 siRNA. Our results suggested that the protective effect of melatonin against prorenin-induced M1 phenotype switching via attenuating mitochondrial oxidative damage depending on UCP2 upregulation in prorenin-treated microglia. [ABSTRACT FROM AUTHOR]

Corticotropin-releasing hormone release is the final common pathway of stress-associated neuroendocrine responses. This study tested how corticotropin-releasing hormone modulates airway vagal preganglionic neurons. Airway vagal preganglionic neurons in neonatal rats were retrogradely labeled with fluorescent dye and identified in medullary slices, and their responses to corticotropin-releasing hormone (200 nmol L −1 ) were examined using whole-cell patch clamp. The results show that under current clamp, corticotropin-releasing hormone (200 nmol L −1 ) depolarized airway vagal preganglionic neurons and significantly increased the rate of their spontaneous firing. Under voltage clamp, corticotropin-releasing hormone caused a tonic inward current and significantly facilitated the spontaneous glutamatergic and GABAergic inputs of these neurons. Corticotropin-releasing hormone had no impact on the spontaneous glycinergic inputs of these neurons. In the preexistence of tetrodotoxin (1 μmol L −1 ), corticotropin-releasing hormone had no impact on the miniature excitatory or inhibitory postsynaptic currents, but still induced a tonic inward current and significantly increased the input resistance. The responses induced by corticotropin-releasing hormone were prevented by Antalarmin hydrochloride (50 μmol L −1 ), an antagonist of type 1 corticotropin-releasing hormone receptors, but insensitive to Astressin 2B (200 nmol L −1 ), an antagonist of type 2 corticotropin-releasing hormone receptors. These results suggest that corticotropin-releasing hormone excites airway vagal preganglionic neurons via activation of its type 1 receptors at multiple sites, which includes a direct postsynaptic excitatory action and presynaptic facilitation of both glutamatergic and GABAergic inputs. In stress, corticotropin-releasing hormone might be able to activate the airway vagal nerves and, consequently, participate in induction or exacerbation of airway disorders. [ABSTRACT FROM AUTHOR]

Summary Here we report the identification and verification of a β-hydroxybutyrate-derived protein modification, lysine β-hydroxybutyrylation (Kbhb), as a new type of histone mark. Histone Kbhb marks are dramatically induced in response to elevated β-hydroxybutyrate levels in cultured cells and in livers from mice subjected to prolonged fasting or streptozotocin-induced diabetic ketoacidosis. In total, we identified 44 histone Kbhb sites, a figure comparable to the known number of histone acetylation sites. By ChIP-seq and RNA-seq analysis, we demonstrate that histone Kbhb is a mark enriched in active gene promoters and that the increased H3K9bhb levels that occur during starvation are associated with genes upregulated in starvation-responsive metabolic pathways. Histone β-hydroxybutyrylation thus represents a new epigenetic regulatory mark that couples metabolism to gene expression, offering a new avenue to study chromatin regulation and diverse functions of β-hydroxybutyrate in the context of important human pathophysiological states, including diabetes, epilepsy, and neoplasia. [ABSTRACT FROM AUTHOR]

Several pieces of evidence indicate that the microglial P2X 7 receptor (P2X 7 R) regulate cardiovascular activities. We explored the possible roles of microglial P2X 7 R in the PVN mediated sympathoexcitatory responses in acute myocardial infarction (AMI) rat. Sprague–Dawley rats underwent coronary artery ligation to induce AMI. The rats received intraperitoneal administration of the P2X 7 R antagonist Brilliant Blue-G (BBG, 25 or 50 mg kg −1 , once a day for 5 days) prior to myocardial ischemia. Other rats received bilateral microinjection of P2X 7 R-siRNA (0.015 or 0.03 nmol 0.1 μl per side, once a day for 2 days) targeting P2X 7 R mRNA into the PVN prior to myocardial ischemia. First, we examined the ATP levels and protein expression P2X 7 R in the PVN in different ischemia time groups, and we found that the change of P2X 7 R was positive correlated with the ATP levels in a time-dependent manner. The double-immunofluorescence evidence showed that P2X 7 R was mainly co-localizated with the microglial marker Iba-1 in the PVN. Second, gene knockdown of P2X 7 R with P2X 7 -siRNA or inhibition of P2X 7 R with BBG reduce the mRNA and protein expression of IL-1β and TNF-α in the PVN of AMI rat. Third, microinjected P2X 7 -siRNA also suppressed the up-regulation of P2X 7 R, oxytocin and vasopressin in the PVN of AMI rats. Fourth, P2X 7 -siRNA and BBG also attenuated the renal sympathetic nerve activity (RSNA) in the AMI rats. Our results indicate that microglial P2X 7 R activation in PVN mediating the production of proinflammatory cytokines that activate oxytocinergic and vasopressinergic neuron, which augmented the RSNA in the AMI rat. [ABSTRACT FROM AUTHOR]

Phellodendron amurenseRupr. produces berberine, a valuable ingredient in Chinese medicine. We examined how berberine content varied in different parts of the tree with age and geography in Northeast China. Berberine levels in root bark, trunk bark, and perennial branch bark, annual branches, and leaves were estimated by high-performance liquid chromatography. Root, trunk, and perennial branch barks had significantly higher berberine content than annual branches and leaves. Moreover, berberine content varied significantly with both longitude and latitude in samples of these three plant parts. The populations growing at low longitude and latitude contained significantly more berberine than those growing at high longitude and latitude. These results provide a scientific basis for the reasonable cultivation and efficient use ofP. amurense. [ABSTRACT FROM AUTHOR]

Abstract: Several pieces of evidence indicate that the rostral ventrolateral medulla (RVLM) is probably one of the key neural structures mediating the pressor effects of orexins in the brain. Nitric oxide synthase/nitric oxide (NOS/NO) system in the RVLM modulates cardiovascular activities. Our experiments were designed to test the hypothesis that orexin-A (OXA) is involved in the mechanism of stress-induced hypertension (SIH) by adjusting NOS/NO system in the RVLM. The stress-induced hypertensive rats (SIHR) model was established by electric foot-shocks and noises. Here we examined the expression of OXA immunoreactive (OXA-IR) cells in the lateral hypothalamus (LH) and the protein level of orexin 1 receptor (OX1R) in the RVLM of SIHR, and we found that the expressions of OXA-IR and OX1R were higher than those of the control group. The double-staining immunohistochemical evidence showed that OX1R immunoreactive (OX1R-IR) cells and neuronal nitric oxide synthase (nNOS) or inducible nitric oxide synthase (iNOS) immunoreactive (IR) cells were co-localizated in the RVLM. Microinjection of OXA (10, 50, 100 pmol/100 nl) into the unilateral (right) RVLM of control rats or SIHR produced pressor and tachycardiac effects in a dose-dependent manner. SB-408124 (100 pmol/100 nl, an antagonist of OX1R) or TCS OX2 29 (100 pmol/100 nl, an antagonist of OX2R) partly abolished the cardiovascular effects of exogenously-administrated OXA into the RVLM of control rats and SIHR, and lowered the increased systolic blood pressure (SBP) and heart rate (HR) of SIHR, with no difference in statistical significance between the two antagonists'' effects. Microinjection into the RVLM of both control and SIHR groups of 7-Ni (0.05 pmol/100 nl, nNOS inhibitor) or Methylene Blue [100 pmol/100 nl, an inhibitor of soluble guanylate cyclase (sGC)] suppressed the OXA-induced increase of SBP and HR, whereas microinjection of AG (1, 10, 100 pmol/100 nl) had no obvious effects on the OXA-induced increase of SBP and HR. Our results indicate that OXA in the RVLM may participate in the central regulation of cardiovascular activities in SIHR, and OX1R and OX2R both have important roles in it. The cardiovascular effects of OXA in the RVLM may be induced by nNOS-derived NO, which activated sGC-associated signaling pathway. [Copyright &y& Elsevier]

Abstract: Aims: To investigate the cardiovascular regulatory mechanism of adenosine A2A receptor (A2AR) in the rostral ventrolateral medulla (RVLM) in acute myocardial ischemic (AMI) rats. Main methods: The animal model of AMI was established by ligating the left anterior descending coronary artery (LAD). The A2AR expression was examined by immunohistochemistry, western blot and real-time PCR. CGS21680 and SCH58261 (an agonist and antagonist of A2AR) were respectively microinjected into the RVLM. In a subgroup of rats, PD98059 (an antagonist of extracellular signal-regulated kinase (ERK1/2)) was microinjected prior to CGS21680 administration. Phosphorylation of ERK1/2 was examined by western blot. Key findings: Our results demonstrated that A2AR immunoreactive positive neurons, the expressions of protein and mRNA of A2AR in the RVLM of AMI group were increased compared with the sham group. Microinjection CGS21680 into the RVLM inhibited mean arterial pressure (MAP) and heart rate (HR) in both AMI and sham groups. The inhibition was significantly greater in AMI group than in sham group. The cardiovascular effects of CGS21680 mentioned above were almost abolished by prior administration of PD98059. The increase of ERK1/2 in the RVLM with the cardiovascular responses was induced by CGS21680 in AMI rats; this effect was also blocked by SCH58261. Significance: This study reveals that the activated A2AR in the RVLM underlies the depressor and bradycardiac responses in AMI rats via phosphorylation of ERK1/2 increasing. [Copyright &y& Elsevier]

Abstract: The functional polymer containing carbazole unit, [(poly(9-(4-vinylbenzyl)-9H-carbazole) (PVBK)], was successfully prepared via nitroxide-mediated living free-radical polymerization of 9-(4-vinylbenzyl)-9H-carbazole (VBK). The controlled features of the polymerization were confirmed by the linear increase in the molecular weight with the monomer conversion while keeping the relative narrow molecular weight distribution (M w/M n ⩽1.51), and successful chain extension with styrene. The resulting polymer absorbed light in the 305–355nm range and exhibited fluorescent emission at 350nm. The fluorescent intensity of the polymer was lower than that of monomer and was affected by the properties of the different solvents, which decreased in the following order: DMF>THF>CHCl3 at the same concentration of carbazole units. The fluorescence intensity of the polymer was apparently influenced by chromophore concentration, and the maximum value was obtained when the carbazole unit concentration was around 8×10−5 mol/L. Moreover, it was shown that the strong fluorescence of PVBK can be quenched by methyl acrylate (MA). [Copyright &y& Elsevier]