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This study was designed to determine the inhibitory effect of astragaloside Ⅳ(AS-Ⅳ), a principal bioactive component extracted from the Chinese medicinal Astragali Radix, on the inflammatory response of vascular endothelial cells induced by angiotensin Ⅱ(Ang Ⅱ), the most major pathogenic factor for cardiovascular diseases, and to clarify the role of calcium(Ca~(2+))/phosphatidylinosi-tol-3-kinase(PI3K)/protein kinase B(Akt)/endothelial nitric oxide synthase(eNOS)/nitric oxide(NO) pathway in the process. To be specific, human umbilical vein endothelial cells(HUVECs) were cultured in the presence of AS-Ⅳ with or without the specific inhibitor of NO synthase(NG-monomethyl-L-arginine, L-NMMA), inhibitor of PI3K/Akt signaling pathway(LY294002), or Ca~(2+)-chelating agent(ethylene glycol tetraacetic acid, EGTA) prior to Ang Ⅱ stimulation. The inhibitory effect of AS-Ⅳ on Ang Ⅱ-induced inflammatory response and the involved mechanism was determined with enzyme-linked immunosorbent assay(ELISA), cell-based ELISA assay, Western blot, and monocyte adhesion assay which determined the fluorescently labeled human monocytic cell line(THP-1) adhered to Ang Ⅱ-stimulated endothelial cells. AS-Ⅳ increased the production of NO by HUVECs in a dose-and time-dependent manner(Plt;0.05) and raised the level of phosphorylated eNOS(Plt;0.05). The above AS-Ⅳ-induced changes were abolished by pretreatment with L-NMMA, LY294002, or EGTA. Compared with the control group, Ang Ⅱ obviously enhanced the production and release of cytokines(tumor necrosis factor-α, interleukin-6), chemokines(monocyte chemoattractant protein-1) and adhesion molecules(intercellular adhesion molecule-1, vascular cellular adhesion molecule-1), and the number of monocytes adhered to HUVECs(Plt;0.05), which were accompanied by the enhanced levels of phosphorylated inhibitor of nuclear factor-κBα protein and activities of nuclear factor-κB(NF-κB)(Plt;0.05). This study also demonstrated that Ang Ⅱ-induced inflammatory response was inhibited by pretreatment with AS-Ⅳ(Plt;0.05). In addition, the inhibitory effect of AS-Ⅳ was abrogated by pretreatment with L-NMMA, LY294002, or EGTA(Plt;0.05). This study provides a direct link between AS-Ⅳ and Ca~(2+)/PI3K/Akt/eNOS/NO pathway in AS-Ⅳ-mediated anti-inflammatory actions in endothelial cells exposed to Ang Ⅱ. The results indicate that AS-Ⅳ attenuates endothelial cell-mediated inflammatory response induced by Ang Ⅱ via the activation of Ca~(2+)/PI3K/Akt/eNOS/NO signaling pathway.

The type-B authentic response regulators (type-B ARRs) are positive regulators of cytokinin signaling and involved in plant growth and stress responses. In this study, we used bioinformatics, RNA-seq, and qPCR to study the phylogenetic and expression pattern of 35 type-B ARRs in

OBJECTIVE: To investigate the risk factors for necrotizing enterocolitis (NEC) in preterm infants, and to establish a scoring model that can predict the development and guide the prevention of NEC. METHODS: A retrospective analysis was performed on the medical data of preterm infants who were admitted to the Department of Neonatology,Bethune First Hospital of Jilin University, from January 2011 to December 2020. These infants were divided into two groups: NEC (298 infants with Bell II stage or above) and non-NEC (300 infants). Univariate and multivariate analyses were performed to identify the factors influencing the development of NEC. A nomogram for predicting the risk of NEC was established based on the factors. The receiver operator characteristic (ROC) curve and the index of concordance (C-index) were used to evaluate the predictive performance of the nomogram. RESULTS: The multivariate logistic regression analysis showed that grade ≥2 intracranial hemorrhage, peripherally inserted central catheterization, breast milk fortifier, transfusion of red cell suspension, hematocrit >49.65%, mean corpuscular volume >114.35 fL, and mean platelet volume >10.95 fL were independent risk factors for NEC (P11.8 fL were protective factors against NEC (P

The fractures and kerogen, which generally exist in the shale, are significant to the CO2 huff-n-puff in the shale reservoir. It is important to study the effects of fractures and kerogen on oil recovery during CO2 huff-n-puff operations in the fracture–matrix system. In this study, a modified CO2 huff-n-puff experiment method is developed to estimate the recovery factors and the CO2 injectivity in the fractured organic-rich shales and tight sandstones. The effects of rock properties, injection pressure, and injection time on the recovery factors and CO2 usage efficiency in shales and sandstones are discussed, respectively. The results show that although the CO2 injectivity in the shale is higher than that in the sandstone with the same porosity; besides, the recovery factors of two shale samples are much lower than that of two sandstone samples. This demonstrates that compared with the tight sandstone, more cycles are needed for the shale to reach a higher recovery factor. Furthermore, there are optimal injection pressures (close to the minimum miscible pressure) and CO2 injection volumes for CO2 huff-n-puff in the shale. Since the optimal CO2 injection volume in the shale is higher than that in the sandstone, more injection time is needed to enhance the oil recovery in the shale. There is a reference sense for CO2 huff-n-puff in the fractured shale oil reservoir for enhanced oil recovery (EOR) purposes.

In recent years, a theme park drives significant attention in tourism industry due to the provision of quality and integrated service, and issuing annual pass cards help the theme park to differentiate long-term customers from short-term ones. Customer Value Analysis is demanded for theme parks to identify potential customers as well as to appraise customer value through the setting of the annual pass. Moreover, customer value often alters from time to time since theme park industry is relevantly competitive and innovation demanded than other industries, and customer preferences are frequently changed. This study provides an early warning system to support the theme park to detect, monitor and analyze the changes of customer value. By applying the aggregated approach based on Rough Set Theory and Recency, Frequency and Monetary architecture, the tourist satisfaction levels can be captured after the aforementioned approach is executed. In addition, the rule comparison approach is contributed to predicting customer behavior from technical viewpoint. This study aims at providing an early correction strategy for the theme park to avoid losing VIP customers and identify latent customers.

A new adenine glycoside 1, along with a known compound 2, was isolated from Brassica rapa. Its structure was elucidated as 5′-deoxy-5′-methylamino-9-(α-L-lyxofuranosyl)adenine on the basis of extensive spectroscopic analyses.

This study aims to investigate the influence of excessive oxidative stress on cardiac injury during acute myocardial ischemia (AMI), with a focus on apoptosis, autophagy, and inflammatory cell infiltration, and to detect the role of hydrogen sulfide (H2S) in this process. We found that SOD1 knockout (KO) mice showed excessive oxidative stress and exacerbated myocardium injury after AMI. Increased apoptosis and inflammation response in the ischemic myocardium contribute to this deterioration, whereas enhanced autophagy plays a protective role. Myocardial inflammation after AMI was much more severe in SOD1 KO mice than in wild-type mice. Pretreatment with the H2S donor NaHS reduced autophagy and apoptosis levels in the ischemic myocardium and alleviated the regional inflammation response in the cardiac tissues of SOD1 KO mice. Moreover, autophagy and apoptosis levels were significantly enhanced in SOD1 knockdown primary neonatal rat cardiomyocytes (NRCMs) under glucose deprivation. Pretreatment with NaHS can partially inhibit this elevation. Taken together, we found that excessive oxidative stress can aggravate cardiac injury during AMI. Exogenous H2S can alleviate cardiac injury during AMI by reducing apoptosis and inflammation response in heart tissues under oxidative stress.

Supplemental Digital Content is available in the text, Osteoporosis (OP) is a disease characterized by decreased bone mineral density (BMD) and an increased risk of osteoporotic fractures. Nutritional factors (including glucose and fats lipids), have been implicated in OP. We hypothesized that the levels of blood glucose and lipids could be biomarkers for predicting the risk of OP. To test this hypothesis, we evaluated the potential relationship between BMD and levels of blood glucose and lipids via a community-based study in China. This was a community-based cross-section analysis, and a total of 8584 cases were investigated. The BMD of the left calcaneus was measured using an ultrasonic bone densitometer. The levels of blood glucose (fasting blood glucose [FBG], 2-h blood glucose [2hBG], and glycosylated hemoglobin [HbAlc]), and lipids (triglyceride [TG], total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], and high-density lipoprotein cholesterol [HDL-C]) were measured and analyzed. In our study population, the levels of FBG, 2hBG, HbAlc, TC, LDL-C and HDL-C were higher in the OP group than in the low bone density and the normal bone density groups, while the levels of HbAlc, TC, and LDL-C in the low bone density group were higher than those in the normal bone density group. In males, the level of blood LDL-C in the low bone density group was higher than that in the normal bone density group. In postmenopausal subjects, the levels of FBG, 2hBG and HbA1C were higher than those in the normal bone density groups, and the level of HbA1C in the low bone density group was higher than that in the normal bone density group. Pearson linear trend analysis demonstrated that BMD was positively associated with TC and LDL-C in males and negatively associated with FBG, 2hBG and HbA1C in postmenopausal females. Moreover, logistic analysis showed that BMD was correlated with TC in premenopausal females and HbA1C in postmenopausal females. OP is generally associated with abnormal levels of blood glucose and/or lipids; nevertheless, the relationship between OP and abnormal levels of blood glucose and/or lipids is complicate and different subpopulations may have different susceptibilities. Therefore, further detailed studies are warranted.

Wave-transparent materials of aluminum borate whisker/phosphate chrome-alumina are synthesized through coating method. It is found that, from the TG-DSC image analysis, there are two endothermic peaks at 120 °C and 180 °C, respectively. Pressure and curing time at this temperature should be increased. The flexural and tensile strength of the composite material reach the maximum when the content of aluminum borate whiskers is 6%.

In this paper, a chemical plant of chromium salt was selected as the typical chromium slag contaminated site. The range and level of chromium in soil were tested by way of digestion and leaching in order to investigate the pollution of chromium slag. Speciation of chromium in soil was simultaneously analyzed by way of Tessier. The results showed that soil around the residue piling yard was polluted by Cr. Concentrations of Cr (VI) and total chromium in soil were both higher than the background value. Speciation analysis indicated that Cr in contaminated soil was mainly in the residual fraction. The data of investigation display chromium slag diffusion rule in horizontal direction is accord with particulate matter non-point source diffusion model.

To determine the effects of transient receptor potential vanilloid type 1 (TRPV1) channel ablation and a chemokine receptor 2 (CCR2) antagonist on salt-sensitive hypertension-induced renal injury.Wild-type (WT) and TRPV1-null mutant (TRPV1(-/-)) mice were subjected to uninephrectomy and deoxycorticosterone acetate (DOCA)-salt treatment for 4 weeks with or without a CCR2 antagonist, RS504393 (n=8 for all the 4 groups). Sham WT and TRPV1(-/-) mice (both n=7) underwent uninephrectomy without receiving DOCA and saline. Systolic blood pressure, urinary excretion of albumin, 8-isoprostane and creatinine clearance for 24 hours were assayed during the experimental period and at the end of the 4-week treatment. The morphological analysis was performed in renal histological sections, including glomerulosclerosis, tubulointerstitial injury, and monocyte/macrophage infiltration.Compared to the corresponding control mice, DOCA-salt treatment in both WT and TRPV1(-/-) mice led to increased systolic blood pressure (SBP), enhanced urinary excretion of albumin and 8-isoprostane, decreased creatinine clearance, increased glomerulosclerosis and tubulointerstitial injury associated with enhanced monocyte/macrophage infiltration (all P0.05), all of which were much more severe in TRPV1(-/-) mice compared to WT mice with the exception of blood pressure (all P0.05). RS5043943 attenuated DOCA-salt-induced changes in renal function and morphology in WT and TRPV1(-/-) mice (all P0.05). There was no difference in blood pressure among DOCA-salt WT and TRPV1(-/-) mice with or without RS505393 with the exception of sham WT and TRPV1(-/-) mice (all P0.05).CCR2 antagonist inhibits DOCA-salt-induced renal injury and monocyte/macrophage infiltration in WT and TRPV1(-/-) mice with the greater in the latter strain. Activation of TRPV1 attenuates salt-sensitive hypertension-induced renal injury possibly via inhibition of CCR2-induced monocyte/macrophage infiltration.

Objective: We tested the hypothesis that occlusion of the superior mesenteric artery induces late preconditioning against myocardial infarction and examined the effects of pharmacological modifiers of inducible nitric oxide synthase activity on the late preconditioning in anesthetized rats. Methods: Rats underwent an intestinal ischemia preconditioning protocol (30 min occlusion of the superior mesenteric artery) or were sham-operated. They were subjected to a sustained 30 min of coronary occlusion and 180 min of reperfusion 24 h later. Results: In rats receiving no pharmacological intervention, the percentage of myocardial infarct within the area at risk and left ventricle was 72±4% and 31±2%, respectively, in sham-operated rats, and these were significantly reduced to 44±4% and 23±2% ( P

Nuclear factor kappa-B (NF-kappaB) is a pleiotropic transcription factor that plays a central role in the immune and inflammatory responses, and is also involved in controlling viral transcription and apoptosis. A critical control in the activation of NF-kappaB is the phosphorylation of its inhibitory factor IkappaBs by IkappaB kinases (IKK-alpha and -beta). Here, we present experiments addressing the regulation and global expression of murine IKK-beta, and localize the IKK-beta gene to mouse chromosome 8A3-A4. IKK-beta was expressed primarily in the liver, kidney and spleen, and at lower levels in the other adult tissues. While IKK-beta was expressed ubiquitously throughout the mouse embryo at 9.5 days, its expression began to be localized to the brain, neural ganglia, neural tube, and liver in the 12.5-day's embryo. At 15.5 days, the expression of IKK-beta was further restricted to specific tissues of the embryo, suggesting that IKK-beta is a developmentally regulated protein kinase. Interestingly, IKK-beta phosphorylated IkappaB constitutively, whereas IKK-alpha was not active in the absence of cell stimulation. Moreover, both IKK-alpha and -beta were activated by hematopoietic progenitor kinase-1 (HPK1) and MAPK/ERK kinase kinase-1 (MEKK1) specifically, suggesting that IkappaB/NF-kappaB is regulated through the HPK1-MEKK1 stress response signaling pathway.

To investigate whether nitric oxide (NO) in the central nervous system is involved in the decrease in renal sympathetic nerve activity (RSNA) during acute cardiac tamponade in conscious rabbits, we examined the effect of 7-nitroindazole (7-NI), a selective inhibitor of neuronal nitric oxide synthase in vivo, on RSNA during acute cardiac tamponade in chronically installed conscious rabbits. Cardiac tamponade was produced by intrapericardial infusion of physiological saline at 2 ml/30 s. Mean arterial pressure (MAP) remained constant initially but RSNA increased to 218±24% when we started injection of physiological saline into the pericardial space. Concomitantly after MAP fell to 51±1 mm Hg by subsequent injection of the saline into the pericardial space, RSNA decreased to 45±6%. If 7-NI (50 mg/kg) was administered intraperitoneally 35 min before the beginning of cardiac tamponade, the decline in RSNA caused by cardiac tamponade was markedly counteracted. Brain nitric oxide synthase (NOS) activity in the cerebral cortex and medulla oblongata, assessed by the conversion of labelled arginine to citrulline, was inhibited by 48% and 44% after the intraperitoneal administration of 7-NI. These results indicate that acute cardiac tamponade elicits a biphasic effect on RSNA, which rises during non-hypotensive period and then falls during hypotension in conscious rabbits. The decrease in RSNA was abolished by treatment with 7-NI, suggesting that the abrupt decrease in RSNA during hypotension induced by acute cardiac tamponade is mediated by NO in the central nervous system.

Nuclear factor kappaB (NF-kappaB) and the Rel family of proteins are pleiotropic transcription factors that play central roles in the immune and inflammatory responses, as well as apoptosis. Here, we identified a serine/threonine protein phosphatase X (PPX; also called protein phosphatase 4 (PP4)) that specifically associated with c-Rel, NF-kappaB p50, and RelA. The amino acid sequences of human and mouse PPX are 100% identical, and the PPX gene was mapped to human chromosome 16 p11.2. Overexpression of PPX, but not catalytically inactive PPX mutants, stimulated the DNA-binding activity of c-Rel and activated NF-kappaB-mediated transcription. These results suggest that PPX is a novel activator of c-Rel/NF-kappaB.

The fibroblast growth factors (FGFs) play key roles in controlling tissue growth, morphogenesis, and repair in animals. We have cloned a novel member of the FGF family, designated FGF-18, that is expressed primarily in the lungs and kidneys and at lower levels in the heart, testes, spleen, skeletal muscle, and brain. Sequence comparison indicates that FGF-18 is highly conserved between humans and mice and is most homologous to FGF-8 among the FGF family members. FGF-18 has a typical signal sequence and was glycosylated and secreted when it was transfected into 293-EBNA cells. Recombinant murine FGF-18 protein (rMuFGF-18) stimulated proliferation in the fibroblast cell line NIH 3T3 in vitro in a heparan sulfate-dependent manner. To examine its biological activity in vivo, rMuFGF-18 was injected into normal mice and ectopically overexpressed in transgenic mice by using a liver-specific promoter. Injection of rMuFGF-18 induced proliferation in a wide variety of tissues, including tissues of both epithelial and mesenchymal origin. The two tissues which appeared to be the primary targets of FGF-18 were the liver and small intestine, both of which exhibited histologic evidence of proliferation and showed significant gains in organ weight following 7 (sometimes 3) days of FGF-18 treatment. Transgenic mice that overexpressed FGF-18 in the liver also exhibited an increase in liver weight and hepatocellular proliferation. These results suggest that FGF-18 is a pleiotropic growth factor that stimulates proliferation in a number of tissues, most notably the liver and small intestine.

To evaluate the effects of Jiashen Prescription (, JSP) on myocardial infarction (MI) size and cardiac function at the early stage of MI in rats.One hundred male Sprague-Dawley rats were subjected to sham-operation or MI induced by ligating the left anterior descending coronary artery. The rats with MI were treated with vehicle, JSP 3 and 6 g/(kg·d), or losartan 10 mg/(kg·d) for 1 week.Compared with the vehicle-treated MI rats, 6 g/(kg·d) JSP reduced MI size 3 days after MI (P0.05), and attenuated the MI-induced increases in left ventricular end-diastolic and end-systolic dimension and decreases in fractional shortening and ejection fraction 1 week after MI (P0.05). In addition, 6 g/(kg·d) JSP and losartan were equally effective in reducing MI size and enhancing cardiac functional recovery.JSP reduces MI size and improves cardiac function after MI, suggesting that JSP has potential as a therapy for MI.

To determine the role of chemokine receptor 2 (CCR2) in the development of salt-sensitive hypertension-induced renal damage.We investigated the renal damage induced by uninephrectomy and deoxycorticosterone acetate (DOCA)-salt in mice treated with or without a selective CCR2 antagonist RS504393 for 4 weeks. Sham mice underwent uninephrectomy without receiving DOCA and saline. Systolic blood pressure, urinary excretion of albumin and 8-isoprostane, creatinine clearance, glomerulosclerosis, renal tubulointerstitial injury, and renal monocyte/macrophage infiltration were measured.DOCA-salt treatment led to increased systolic blood pressure, increased urinary excretion of albumin and 8-isoprostane, decreased creatinine clearance, glomerulosclerosis, renal tubulointerstitial injury, and renal monocyte/macrophage infiltration compared with the sham mice (P0.05). All of them were prevented by CCR2 inhibition (P0.05).Blockade of CCR2 prevents renal damage induced by DOCA-salt treatment, suggesting that CCR2-mediated monocyte/macrophage infiltration may contribute to salt-sensitive hypertension-induced renal injury.

Patchouli alcohol (PA) is a kind of methanol extracted from traditional Chinese medicine Pogostemonis Herba. Our research aimed to observe the anti-influenza virus role of PA in vitro. 16HBE (human respiratory epithelial cell) was infected by H1N1 (A/FM1/1/47) to set the cell model. Then the 16HBE was co-cultivated with three kinds of immune cells: dendritic cells, macrophages, and monocytes, PA (the concentration is 10 μg/mL) was added as a treatment intervention for 24 h. The immune cells and the supernate were collected for RT-PCR and ELISA detection related to RLH (RIG-1-like helicases) pathway. Results showed that the IL-4 and IFN-γ in supernate were increased after H1N1 infection, and the PA treatment suppressed the expression of cytokines and the mRNA of RLH pathway. PA anti-influenza virus may through regulate the RLH singal pathway.

Objectives The purpose of this study was to evaluate the effects of interleukin-13 (IL-13) polymorphisms on the risk of asthma using a meta-analysis. Design and methods Fifteen publications were identified by searching Pubmed, Embase, ISI, OVID, and EBSCO databases. Odds ratios with corresponding 95% confidence intervals were computed to estimate the association between IL-13 polymorphisms and risk of asthma. Results The polymorphisms of R130Q (rs20541) and -1112C/T (rs1800925) in IL-13 gene were associated with significantly increased risks of asthma in overall analyses. Subgroup analyses showed that the elevated risks occurred in adult-onset asthma, Caucasians, and high quality studies. Conclusions This meta-analysis provides evidence that the R130Q and -1112C/T polymorphisms in IL-13 are risk factors for asthma.

Physical localization of ribosomal genes in diploid and tetraploid alfalfa (Medicago. sativa) was studied using fluorescent in situ hybridization (FISH). It was revealed that 45s gene was only located at nucleolus organizer region (NOR) with a single locus in both diploid and tetraploid alfalfa, while 5s gene had 2-3 loci on chromosomes. Using the genomic DNA from M. coerulea and M. falcata as probe to hybridize with tetraploid species in alfalfa, both diploid species were successfully hybridized with tetraploid chromosomes, only showing the difference in hybridization signals in different numbers of chromosomes. Chromosomes of alfalfa exhibited DAPI banding by FISH analysis. In general, the patterns of distribution of DAPI banding were consistent with C-banding for M. coerulea. The possible origination of tetraploid alfalfa was discussed based on DAPI banding patterns and FISH analysis for ribosomal genes .

Objective: The aim of this study was to investigate the role of inducible nitric oxide synthase (iNOS) as a trigger in lipopolysaccharide (LPS)-induced late preconditioning against myocardial infarction. Methods: Rats were pretreated intraperitoneally with two different doses of LPS (0.5 or 2.5 mg/kg) or normal saline (control) 24 h prior to lethal myocardial ischemia. Subsequently, all rats were subjected to a sustained 30-min coronary occlusion followed by 180-min reperfusion. In the second study, total RNA and protein were extracted from myocardium of the control and LPS-treated rats (after 4, 6 and 24 h of treatment) for reverse transcription-polymerase chain reaction and Western blot analysis. Results: In LPS (2.5 mg/kg, but not 0.5 mg/kg)-treated rats receiving no pharmacological intervention, the percentage of myocardial infarct within the area at risk and left ventricle was significantly reduced to 42±4 and 24±2% ( P

Objective: The present study was designed to test the hypothesis that intestinal ischemia results in an early preconditioning against myocardial infarction and that the mechanism of the early preconditioning involves the activation of protein kinase C-mitochondrial KATP channel signaling pathway in anesthetized rats. Methods: Rats were either preconditioned with a 25-min occlusion of the superior mesenteric artery followed by 15 min of reperfusion or underwent a 40-min sham period. Subsequently, all rats were subjected to a sustained 30 min of coronary occlusion and 180 min of reperfusion. Infarct size was determined by triphenyltetrazolium chloride staining. Results: In sham-operated rats receiving no pharmacological intervention, the percentage of myocardial infarct within the area at risk and left ventricle was 73±4% and 31±2%, respectively, and these were significantly reduced to 44±4% and 23±1% ( P

SUMMARY 1. The present study was planned to: (i) determine whether the baroreflex control of heart rate (HR) and renal sympathetic nerve activity (RSNA) was attenuated during reperfusion of short-term ischaemic myocardium; and (ii) study whether blockade of prostaglandin synthesis with indomethacin reversed the inhibitory baroreflex. 2. Arterial pressure was lowered with intravenous sodium nitroprusside before coronary occlusion and 3 min after release of a 5 min occlusion of the left circumflex coronary artery in anaesthetized rabbits. The protocol was repeated 20 min after indomethacin (5 mg/kg, i.v.) or indomethacin vehicle (50 mmol/L tris(hydroxymethyl)aminomethane buffer, pH 8.4) treatment. In addition, this study was performed in a group of vagotomized rabbits. 3. Before indomethacin treatment, the slope of the mean arterial pressure (MAP)–RSNA relationship decreased from –3.3±0.77 to –2.01±0.69% change in RSNA/mmHg (P < 0.05) during reperfusion of ischaemic myocardium in intact rabbits. The decrease in the slope was reversed by administration of indomethacin. However, the decrease in the slope was not reversed by indomethacin vehicle. Furthermore, the reduction in the slope of the MAP–RSNA relationship during reperfusion of ischaemic myocardium was abolished in vagotomized rabbits. However, there was no inhibition of the slope of the MAP–HR relationship during reperfusion of ischaemic myocardium in either intact or vagotomized rabbits. 4. In conclusion, our data suggest that prostaglandins released by ischaemic myocardium can attenuate the baroreflex-mediated response of RSNA to lowered arterial pressure via vagal afferents during reperfusion of short-term ischaemic myocardium.

The fibroblast growth factors (FGFs) play crucial roles in controlling embryonic development, cell growth, morphogenesis, and tissue repair in animals. Furthermore, FGFs may have a role in angiogenesis and may be involved in tumor invasion and metastasis. Here, we present the cloning and sequence of human FGF-18, a novel member of the FGF family. Sequence comparison indicates that FGF-18 is conserved with the other FGFs and most homologous to FGF-8 among the FGF family members. We showed that human FGF-18 was expressed primarily in the heart, skeletal muscle, and pancreas, and at lower levels in the other tissues. FGF-18 was also expressed at low levels in certain cancer cell lines. FGF-18 contains a typical signal peptide and was secreted when it was transfected into mammalian cells. Recombinant FGF-18 protein stimulated proliferation in the fibroblast cell line NIH3T3 in a dose-dependent manner, suggesting that FGF-18 is a functional growth factor. Finally, the FGF-18 gene was evolutionarily conserved, and localized to human chromosome 14p11.

Activation of the transcription factor nuclear factor kappa B (NF-kappaB) is regulated by phosphorylation, ubiquitination, and degradation of its inhibitory factor IkappaB. Very recently, two closely related serine/threonine kinases have been identified as IkappaB kinases which are essential for IkappaB phosphorylation and NF-kappaB activation. Here, we isolated the full-length human cDNA clones encoding these two IkappaB kinases, IKK-alpha and IKK-beta. Both polypeptides contain a conserved amino-terminal kinase domain, a leucine zipper motif and a helix-loop-helix domain at their carboxyl terminus. We showed that IKK-alpha and IKK-beta were coexpressed in most human adult tissues as well as in different developmental stages of mouse embryos, suggesting that they may cooperate in the cells. The IKK-alpha and IKK-beta genes are distinct but evolutionarily conserved. Moreover, the IKK-alpha gene locus was mapped to human chromosome 10q24, whereas the IKK-beta gene locus was localized to human chromosome 8p11.2. These results indicated that both genes are not clustered on the same chromosome; nevertheless, both genes may be still regulated similarly during development and in adult tissues.

The function of the tumor suppressor protein p53 is modulated by post-translational events, primarily by phosphorylation. p53 is phosphorylated at multiple sites by a variety of protein kinases depending on the cellular environment. It has been suggested that serine 34 of mouse p53 is specifically phosphorylated by a stress- activated protein kinase in response to ultraviolet radiation. Since serine 34 is a major site of phosphorylation of mouse p53 in vivo and its specific protein kinase is still not definitively identified yet, we have examined the c-Jun N-terminal kinase 1 (JNK1) activity on p53 by expressing JNK1 in 293T cells. We show here that activated JNK1 phosphorylates mouse p53 specifically at serine 34 in vitro, while a dominanant-negative JNK1 mutant does not phosphorylate p53. More importantly, JNK1 associates with p53 in vivo, with or without activation, confirming that JNK1 is indeed a p53 kinase. Interestingly, activated JNK2 and JNK3 also phosphorylate serine 34 of mouse p53. Furthermore, JNK2 and JNK3 also associate with p53 in vivo, indicating that not only JNK1, but also JNK2 and JNK3 are p53 N-terminal serine 34 kinases. Phosphorylation of p53 by JNKs may play an important role in nuclear signal transduction in response to environmental stress or tumorigenic agents.

The p38 mitogen-activated protein kinases (MAPK) play a crucial role in stress and inflammatory responses and are also involved in activation of the human immunodeficiency virus gene expression. We have isolated the murine cDNA clones encoding p38-delta MAPK, and we have localized the p38-delta gene to mouse chromosome 17A3-B and human chromosome 6p21.3. By using Northern and in situ hybridization, we have examined the expression of p38-delta in the mouse adult tissues and embryos. p38-delta was expressed primarily in the lung, testis, kidney, and gut epithelium in the adult tissues. Although p38-delta was expressed predominantly in the developing gut and the septum transversum in the mouse embryo at 9.5 days, its expression began to be expanded to many specific tissues in the 12.5-day embryo. At 15.5 days, p38-delta was expressed virtually in most developing epithelia in embryos, suggesting that p38-delta is a developmentally regulated MAPK. Interestingly, p38-delta and p38-alpha were similar serine/threonine kinases but differed in substrate specificity. Overall, p38-delta resembles p38-gamma, whereas p38-beta resembles p38-alpha. Moreover, p38-delta is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7, suggesting that p38-delta is a unique stress-responsive protein kinase.