Biomedical subjects

Aihua Li

Publications and source records attributed to Aihua Li.

At least 19 recordsLinked to original sources

PubMed2006

Ghrelin stimulates angiogenesis in human microvascular endothelial cells: Implications beyond GH release.

Ghrelin, a peptide hormone isolated from the stomach, releases growth hormone and stimulates appetite. Ghrelin is also expressed in pancreas, kidneys, cardiovascular system and in endothelial cells. The precise role of ghrelin in endothelial cell functions remains unknown. We examined the expression of ghrelin and its receptor (GHSR1) mRNAs and proteins in human microvascular endothelial cells (HMVEC) and determined whether ghrelin affects in these cells proliferation, migration and in vitro angiogenesis; and whether MAPK/ERK2 signaling is important for the latter action. We found that ghrelin and GHSR1 are constitutively expressed in HMVEC. Treatment of HMVEC with exogenous ghrelin significantly increased in these cells proliferation, migration, in vitro angiogenesis and ERK2 phosphorylation. MEK/ERK2 inhibitor, PD 98059 abolished ghrelin-induced in vitro angiogenesis. This is the first demonstration that ghrelin and its receptor are expressed in human microvascular endothelial cells and that ghrelin stimulates HMVEC proliferation, migration, and angiogenesis through activation of ERK2 signaling.

Cell Line↗

PubMed2006

Neurokinin-1 receptor-expressing neurons in the ventral medulla are essential for normal central and peripheral chemoreception in the conscious rat.

Neurokinin-1 receptor immunoreactive (NK1R-ir) neurons and processes are widely distributed within the medulla, prominently at central chemoreceptor sites. Focal lesions of NK1R-ir neurons in the medullary raphe or the retrotrapezoid nucleus partially reduced the CO(2) response in conscious rats. We ask if NK1R-ir cells and processes over a wide region of the ventral medulla are essential for central and peripheral chemoreception by cisterna magna injection of SSP-SAP, a high-affinity version of substance P-saporin. After 22 days, NK1R-ir cell loss was -79% in the retrotrapezoid nucleus and -65% in the A5 region, which lie close to the ventral surface, and -38% in the medullary raphe and -49% in the pre-Bötzinger complex/rostral ventral respiratory group, which lie deeper. Dorsal chemoreceptor sites, the caudal nucleus tractus solitarius and the A6 region, were unaffected. At 8 and 22 days, these lesions produced 1) hypoventilation during air breathing in wakefulness ( approximately 8%) and in non-rapid eye movement (NREM) ( approximately 9%) and rapid eye movement ( approximately 14%) sleep, as measured over a 4-h period; 2) a substantially reduced ventilatory response to 7% CO(2) by 61% in wakefulness and 46-57% in NREM sleep; and 3) a decreased ventilatory response to 12% O(2) by 40% in wakefulness and 35% in NREM sleep at 8 days, with partial recovery by 22 days. NK1R-ir neurons in the ventral medulla are essential for normal central chemoreception, provide a drive to breathe, and modulate the peripheral chemoreceptor responses. These effects are not state dependent.

Animals↗

PubMed2006

Simultaneous inhibition of caudal medullary raphe and retrotrapezoid nucleus decreases breathing and the CO2 response in conscious rats.

The medullary raphe (MR) and the retrotrapezoid nucleus (RTN) in the ventral medulla are two of many central chemoreceptor sites. We examine their combined function in conscious rats by focal inhibition using microdialysis. Inhibition of RTN neurons with the GABA(A) receptor agonist muscimol, with simultaneous dialysis of artificial cerebrospinal fluid (ACSF) in or near to the caudal MR, causes hypoventilation (decrease in the ratio of minute ventilation to oxygen consumption, V(E)/V(O2)) and reduces the ventilatory response to 7% CO(2) by 24%. Inhibition of caudal MR serotonergic neurons with the 5-HT(1A) receptor agonist (R)-(+)-8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT), with simultaneous dialysis of ACSF in or near to the RTN, causes hypoventilation but has no significant effect on the CO(2) response. Inhibition of both the RTN and the caudal MR simultaneously produces enhanced hypoventilation and a 51% decrease in the CO(2) response. The effects of treatment on the CO(2) response are similar in wakefulness and in non-rapid eye movement sleep. Comparison of the effect of 8-OH-DPAT microdialysed into a more rostral portion of the MR, where the CO(2) response is reduced by 22%, demonstrates heterogeneity within the MR of the function of serotonergic neurons in breathing. We conclude that serotonergic neurons within the caudal MR provide a non-CO(2)-dependent tonic drive to breathe and potentiate the effects of RTN neurons that contribute to a resting chemical 'drive to breathe' as well as the response to added CO(2). These effects of caudal MR serotonergic neurons could be at a chemoreceptor site, e.g. the RTN, or at 'downstream' sites involved in rhythm and pattern generation.

Animals↗

PubMed2006

Central chemoreception 2005: a brief review.

This brief review will place recent findings on specific neurons and receptors identified as putative central chemoreceptors, namely glutamatergic and serotonergic neurons and purogenic receptors, into the context of our working hypothesis that central chemoreception is a distributed property.

Anesthesia↗

PubMed2006

The nonspecific anti-inflammatory therapy with methotrexate for patients with chronic heart failure.

BACKGROUND: Inflammatory mediators play an important role in the pathogenesis of chronic heart failure (CHF). Methotrexate (MTX) is used in the treatment of inflammatory-mediated diseases (eg, rheumatoid arthritis) because it modulates the expression of numerous inflammatory cytokines. However, no studies have assessed the effects of MTX on plasma levels of inflammatory mediators in patients with CHF. METHODS: In a prospective, randomized, placebo-controlled, single-blind study, 71 patients receiving conventional treatment were randomly allocated to either MTX group (7.5 mg once a week, n = 35) or placebo group (n = 36) with a follow-up of 12 weeks. The effects of MTX on plasma cytokine expression, left ventricular ejection fraction, left ventricular end-diastolic dimension, New York Heart Association (NYHA) functional class, 6-minute walk test distance, and quality of life (QOL) were determined in patients with CHF. RESULTS: Sixty-two patients completed the study. The circulating levels of inflammatory mediators in patients with CHF were markedly elevated compared with healthy controls (P < or = .002). Methotrexate (n = 30) reduced plasma levels of tumor necrosis factor alpha (-15.6%, P < .05), interleukin 6 (-21.8%, P < .01), monocyte chemoattractant protein-1 (-22.6%, P < .01), soluble intercellular adhesion molecule-1 (-19.2%, P < .05), and C-reactive protein (-27.2%, P < .01) compared with baseline. Furthermore, interleukin 10 (15.8 %, P < .05) and soluble IL-1 receptor antagonist (36.1%, P < .01) expression was increased, whereas improvements in NYHA classification, 6-minute walk test distance, and QOL were found compared with baseline. Monocyte chemoattractant protein-1 expression was lower and soluble IL-1 receptor antagonist expression higher in the MTX than placebo group (n = 32). Furthermore, the left ventricular ejection fraction, left ventricular end-diastolic dimension, and incidence of main adverse cardiac events between the 2 groups were similar. CONCLUSION: These results suggest that the addition of MTX to conventional therapy for CHF has significant anti-inflammatory effects and improves NYHA functional class, 6-minute walk test distance, and QOL.

Anti-Inflammatory Agents↗

PubMed2005

Ventilatory effects of muscimol microdialysis into the rostral medullary raphé region of conscious rats.

We hypothesized that inhibition of the rostral medullary raphe region (MRR), a putative central chemoreceptor location, with the GABA(A) receptor agonist muscimol would decrease ventilatory responses to hypercapnia and hypoxia in conscious rats, and that its known effect at this site on body temperature might alter its effect upon these ventilatory responses. At ambient temperatures of 24.5-26.5 degrees C (Cool), microdialysis of 1mM muscimol into the MRR significantly decreased body temperature by approximately 0.5 degrees C, increased the ventilatory response to 7% CO(2) and decreased the response to 10% O(2). At ambient temperatures of 29.5-30.5 degrees C (Warm), 1 mM muscimol microdialysis no longer decreased body temperature and increased the ventilatory response to hypercapnia and to hypoxia. Muscimol did not significantly affect the VE/VO2 ratio at either temperature. Muscimol significantly increased the hypercapnic ventilatory responses in Cool and Warm conditions and the hypoxic response in Warm conditions, which indicates the presence of an inhibitory effect of rostral MRR neurons sensitive to muscimol. In the Cool condition the ventilatory response to hypoxia is inhibited but appropriately so for the lower VO2 .

Analysis of Variance↗

PubMed2005

Catecholamine neurones in rats modulate sleep, breathing, central chemoreception and breathing variability.

Brainstem catecholamine (CA) neurones have wide projections and an arousal-state-dependent activity pattern. They are thought to modulate the processing of sensory information and also participate in the control of breathing. Mice with lethal genetic defects that include CA neurones have abnormal respiratory control at birth. Also the A6 region (locus coeruleus), which contains CA neurones sensitive to CO(2) in vitro, is one of many putative central chemoreceptor sites. We studied the role of CA neurones in the control of breathing during sleep and wakefulness by specifically lesioning them with antidopamine beta-hydroxylase-saporin (DBH-SAP) injected via the 4th ventricle. After 3 weeks there was a 73-84% loss of A5, A6 and A7 tyrosine hydroxylase (TH) immunoreactive (ir) neurones along with 56-60% loss of C1 and C2 phenyl ethanolamine-N-methyltransferase (PNMT)-ir neurones. Over the 3 weeks, breathing frequency decreased significantly during air and 3 or 7% CO(2) breathing in both wakefulness and non-REM (NREM) sleep. The rats spent significantly less time awake and more time in NREM sleep. REM sleep time was unaffected. The ventilatory response to 7% CO(2) was reduced significantly in wakefulness at 7, 14 and 21 days (-28%) and in NREM sleep at 14 and 21 days (-26%). Breathing variability increased in REM sleep but not in wakefulness or NREM sleep. We conclude that CA neurones (1) promote wakefulness, (2) participate in central respiratory chemoreception, (3) stimulate breathing frequency, and (4) minimize breathing variability in REM sleep.

Animals↗

PubMed2005

Medullary serotonergic neurones modulate the ventilatory response to hypercapnia, but not hypoxia in conscious rats.

Serotonergic neurones in the mammalian medullary raphe region (MRR) have been implicated in central chemoreception and the modulation of the ventilatory response to hypercapnia, and may also be involved in the ventilatory response to hypoxia. In this study, we ask whether ventilatory responses across arousal states are affected when the 5-hydroxytryptamine 1A receptor (5-HT1A) agonist (R)-(+)-8-hydroxy-2(di-n-propylamino)tetralin (DPAT) is microdialysed into the MRR of the unanaesthetized adult rat. Microdialysis of 1, 10 and 30 mM DPAT into the MRR significantly decreased absolute ventilation values(VE) during 7% CO2 breathing by 21%, 19% and 30%, respectively, in wakefulness compared to artificial cerebrospinal fluid (aCSF) microdialysis, due to decreases in tidal volume (VT) and not in frequency (f), similar to what occurred during non-rapid eye movement (NREM) sleep. The concentration-dependence of the hypercapnic ventilatory effect might be due to differences in tissue distribution of DPAT. DPAT (30 mM) changed room air breathing pattern by increasing f and decreasing VT. As evidenced by a sham control group, repeated experimentation and microdialysis of aCSF alone had no effect on the ventilatory response to 7% CO2 during wakefulness or sleep. Unlike during hypercapnia, microdialysis of 30 mM DPAT into the MRR did not change the ventilatory response to 10% O2. Additionally, 10 and 30 mM DPAT MRR microdialysis decreased body temperature, and 30 mM DPAT increased the percentage of experimental time in wakefulness. We conclude that serotonergic activity in the MRR plays a role in the ventilatory response to hypercapnia, but not to hypoxia, and that MRR 5-HT1A receptors are also involved in thermoregulation and arousal.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2005

Autocrine role of interleukin-8 in induction of endothelial cell proliferation, survival, migration and MMP-2 production and angiogenesis.

Interleukin-8 (IL-8/CXCL8), a paracrine angiogenic factor, modulates multiple biologic functions in CXCR1 and CXCR2 expressing endothelial cells. Several reports suggest that inflammation, infection, cellular stress and tumor presence regulate IL-8 production in endothelial cells. In the present study, we test the hypothesis that IL-8 regulates multiple biological effects in endothelial cells in an autocrine manner. We examined the autocrine role of IL-8 in regulating angiogenesis by using a neutralizing antibody to IL-8, CXCR1 or CXCR2 in human vein umbilical endothelial cell (HUVEC) and human dermal microvascular endothelial cell (HMEC). Neutralizing antibody to IL-8, CXCR1 or CXCR2 inhibited endothelial cell proliferation, and MMP-2 production as compared to cells cultured with medium alone or control antibody. In addition, we observed that the number of apoptotic cells was significantly higher in anti-IL-8, anti-CXCR1 and anti-CXCR2 treated endothelial cells, which coincided with decreased survival-associated gene expression. We observed reduced migration of endothelial cells treated with anti-IL-8 and anti-CXCR2 antibody, but not anti-CXCR1 antibody as compared to controls. Further, we observed an inhibition of capillary tube formation and neovascularization following treatment with anti-IL-8, anti-CXCR1 and anti-CXCR2 antibodies. Together these data suggest that IL-8 functions as an important autocrine growth and angiogenic factor in regulating multiple biological activities in endothelial cells.

Autocrine Communication↗

PubMed2005

Inactivation of CtIP leads to early embryonic lethality mediated by G1 restraint and to tumorigenesis by haploid insufficiency.

CtIP interacts with a group of tumor suppressor proteins including RB (retinoblastoma protein), BRCA1, Ikaros, and CtBP, which regulate cell cycle progression through transcriptional repression as well as chromatin remodeling. However, how CtIP exerts its biological function in cell cycle progression remains elusive. To address this issue, we generated an inactivated Ctip allele in mice by inserting a neo gene into exon 5. The corresponding Ctip(-/-) embryos died at embryonic day 4.0 (E4.0), and the blastocysts failed to enter S phase but accumulated in G(1), leading to a slightly elevated cell death. Mouse NIH 3T3 cells depleted of Ctip were arrested at G(1) with the concomitant increase in hypophosphorylated Rb and Cdk inhibitors, p21. However, depletion of Ctip failed to arrest Rb(-/-) mouse embryonic fibroblasts (MEF) or human osteosarcoma Saos-2 cells at G(1), suggesting that this arrest is RB dependent. Importantly, the life span of Ctip(+/-) heterozygotes was shortened by the development of multiple types of tumors, predominantly, large lymphomas. The wild-type Ctip allele and protein remained detectable in these tumors, suggesting that haploid insufficiency of Ctip leads to tumorigenesis. Taken together, this finding uncovers a novel G(1)/S regulation in that CtIP counteracts Rb-mediated G(1) restraint. Deregulation of this function leads to a defect in early embryogenesis and contributes, in part, to tumor formation.

Animals↗

PubMed2004

Chronic fluoxetine microdialysis into the medullary raphe nuclei of the rat, but not systemic administration, increases the ventilatory response to CO2.

In conscious rats, focal CO2 stimulation of the medullary raphe increases ventilation, whereas interference with serotonergic function here decreases the ventilatory response to systemic hypercapnia. We sought to determine whether repeated administration of a selective serotonin reuptake inhibitor in this region would increase the ventilatory response to hypercapnia in unanesthetized rats. In rats instrumented with electroencephalogram-electromyogram electrodes, 250 or 500 microM fluoxetine or artificial cerebrospinal fluid (aCSF) was microdialyzed into the medullary raphe for 30 min daily over 15 days. To compare focal and systemic treatment, two additional groups of rats received 10 mg x kg(-1) x day(-1) fluoxetine or vehicle systemically. Ventilation was measured in normocapnia and in 7% CO2 before treatment (day 0), acutely (days 1 or 3), on day 7, and on day 15. There was no change in normocapnic ventilation in any treatment group. Rats that received 250 microM fluoxetine microdialysis showed a significant 13% increase in ventilation in wakefulness during hypercapnia on day 7, due to an increase in tidal volume. In rats microdialyzed with 500 microM fluoxetine, there were 16 and 32% increases in minute ventilation during hypercapnia in wakefulness and sleep on day 7, and 20 and 28% increases on day 15, respectively, again due to increased tidal volume. There was no change in the ventilatory response to CO2 in rats microdialyzed with aCSF or in systemically treated rats. Chronic fluoxetine treatment in the medullary raphe increases the ventilatory response to hypercapnia in an unanesthetized rat model, an effect that may be due to facilitation of chemosensitive serotonergic neurons.

Analysis of Variance↗

PubMed2004

Somatic mutation of p53 leads to estrogen receptor alpha-positive and -negative mouse mammary tumors with high frequency of metastasis.

Approximately 70% of human breast cancers are estrogen receptor alpha (ERalpha)-positive, but the origins of ERalpha-positive and -negative tumors remain unclear. Hormonal regulation of mammary gland development in mice is similar to that in humans; however, most mouse models produce only ERalpha-negative tumors. In addition, these mouse tumors metastasize at a low rate relative to human breast tumors. We report here that somatic mutations of p53 in mouse mammary epithelial cells using the Cre/loxP system leads to ERalpha-positive and -negative tumors. p53 inactivation under a constitutive active WAPCre(c) in prepubertal/pubertal mice, but not under MMTVCre in adult mice, leads to the development of ERalpha-positive tumors, suggesting that target cells or developmental stages can determine ERalpha status in mammary tumors. Importantly, these tumors have a high rate of metastasis. An inverse relationship between the number of targeted cells and median tumor latency was also observed. Median tumor latency reaches a plateau when targeted cell numbers exceed 20%, implying the existence of saturation kinetics for breast carcinogenesis. Genetic alterations commonly observed in human breast cancer including c-myc amplification and Her2/Neu/erbB2 activation were seen in these mouse tumors. Thus, this tumor system reproduces many important features of human breast cancer and provides tools for the study of the origins of ERalpha-positive and -negative breast tumors in mice.

Alleles↗

PubMed2004

Inhibition of medullary raphe serotonergic neurons has age-dependent effects on the CO2 response in newborn piglets.

Medullary raphé serotonergic neurons are chemosensitive in culture and are situated adjacent to blood vessels in the brain stem. Selective lesioning of serotonergic raphé neurons decreases the ventilatory response to systemic CO2 in awake and sleeping adult rats. Abnormalities in the medullary serotonergic system, including the raphé, have been implicated in the sudden infant death syndrome (48). In this study, we ask whether serotonergic neurons in the medullary raphé and extra-raphé regions are involved in the CO2 response in unanesthetized newborn piglets, 3-16 days old. Whole body plethysmography was used to examine the ventilatory response to 5% CO2 before and during focal inhibition of serotonergic neurons by 8-hydroxy-2-di-n-propylaminotetralin (8-OH-DPAT), a 5-HT1A receptor agonist. 8-OH-DPAT (10 or 30 mM in artificial cerebrospinal fluid) decreased the CO2 response in wakefulness in an age-dependent manner, as revealed by a linear regression analysis that showed a significant negative correlation (P < 0.001) between the percent change in the CO2 response and piglet age. Younger piglets showed an exaggerated CO2 response. Control dialysis with artificial cerebrospinal fluid had no significant effect on the CO2 response. Additionally, 8-OH-DPAT increased blood pressure and decreased heart rate independent of age (P < 0.05). Finally, sleep cycling was disrupted by 8-OH-DPAT, such that piglets were awake more and asleep less (P < 0.05). Because of the fragmentary sleep data, it was not possible to examine the CO2 response in sleep. Inhibition of serotonergic medullary raphé and extra-raphé neurons decreases ventilatory CO2 sensitivity and alters cardiovascular variables and sleep cycling, which may contribute to the sudden infant death syndrome.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2004

Medullary serotonergic neurones and adjacent neurones that express neurokinin-1 receptors are both involved in chemoreception in vivo.

Neurokinin-1 receptor (NK1R)-expressing neurones that are involved in chemoreception at the retrotrapezoid nucleus (Nattie & Li, 2002b) are also prominent at locations that contain medullary serotonergic neurones, which are chemosensitive in vitro. In medullary regions containing both types, we evaluated their role in central chemoreception by specific cell killing. We injected (2 x 100 nl) (a) substance P-saporin (SP-SAP; 1 microm) to kill NK1R-expressing neurones, (b) a novel conjugate of a monoclonal antibody to the serotonin transporter (SERT) and saporin (anti-SERT-SAP; 1 microm) to kill serotonergic neurones, or (c) SP-SAP and anti-SERT-SAP together to kill both types. Controls received IgG-SAP injections (1 microm). There was no double-labelling of NK1R-immunoreactive (ir) and tryptophan-hydroxylase (TPOH)-ir neurones. Cell (somatic profile) counts showed that NK1R-ir neurones in the SP-SAP group were reduced by 31%; TPOH-ir neurones in the anti-SERT-SAP group by 28%; and NK1R-ir and TPOH-ir neurones, respectively, in the combined lesion group by 55% and 31% (P < 0.001; two-way ANOVA; P < 0.05, Tukey's post hoc test). The treatments had no significant effect on sleep/wake time, body temperature, or oxygen consumption but all three reduced the ventilatory response to 7% inspired CO(2) in wakefulness and sleep by a similar amount. SP-SAP treatment decreased the averaged CO(2) responses (3, 7 and 14 days after lesions) in wakefulness and sleep by 21% and 16%, anti-SERT-SAP decreased the responses by 15% and 18%, and the combined treatment decreased the responses by 12% and 12% (P < 0.001; two-way ANOVA; P < 0.05, Tukey's post hoc test). We conclude that separate populations of serotonergic and adjacent NK1R-expressing neurones in the medulla are both involved in central chemoreception in vivo.

Animals↗

PubMed2004

Constitutive expression of growth regulated oncogene (gro) in human colon carcinoma cells with different metastatic potential and its role in regulating their metastatic phenotype.

The purpose of this study was to examine the expression and functional significance of the growth-regulated oncogene (gro) family in human colon carcinoma growth and metastasis. We examined constitutive expression of CXCL1 (gro-alpha), CXCL2 (gro-beta), CXCL3 (gro-gamma) and their receptor, CXCR2 in human colon carcinoma cells with different metastatic potentials. Non-metastatic and low metastatic cells expressed lower levels of CXCL1 and CXCR2 mRNA and protein as compared to high metastatic colon carcinoma cells. No difference in CXCL2 and CXCL3 mRNA expression levels was observed. Colon carcinoma cells expressing higher levels of CXCL1 exhibit increased proliferation and invasive potential. Furthermore, exogenous addition of recombinant human CXCL1 significantly enhanced the proliferation and invasiveness of colon carcinoma cells. Furthermore, treatment of KM12C cells with exogenous CXCL1 enhanced their invasiveness. Neutralizing antibody to CXCL1 in combination with antibody to CXCR2 inhibited highly metastatic KM12L4 (high CXCL1 expressor) cell proliferation. These data demonstrate that the constitutive expression of CXCL1 and its receptor CXCR2 is associated with metastatic potential and modulates colon cancer cell proliferation and an invasive phenotype.

Animals↗

PubMed2004

[Pharmacological mechanism of Semen Litchi on antagonizing insulin resistance in rats with type 2 diabetes].

OBJECTIVE: To investigate the pharmacological mechanism of Semen Litchi water extract (SL) on enhancing insulin sensitivity in type 2 diabetic rats (T2DR) with insulin resistance (IR). METHODS: The effects of SL were observed on serum contents of fasting glucose (FSG), blood urea nitrogen (BUN), creatine (Cr), total proteins (TP), albumin (A), malondialdehyde (MDA), total cholesterols (TC), triacylglycerol (TG), free fatty acid (FFA), leptin, tumor necrosis factor-alpha (TNF-alpha), fasting insulin (Fins) and index of insulin sensitivity (ISI), and activities of superoxide dismutase (SOD), alanine aminotransferase (ALT), aspartate aminotransferase (AST) in T2DR-IR. RESULTS: In T2DR-IR, SL could lower concentrations of FSG, TC, TG, FFA, leptin, TNF-alpha and Fins (P < 0.05-0.01), increase ISI (P < 0.01), reform the hyperinsulinemia and insulin sensitivity, decrease the levels of BUN, Cr and the activities of ALT, AST, increase concentration of TP, A (P < 0.05-0.01), recover the hepatic and nephric functions, increase the activity of SOD and decrease content of MDA (P < 0.01). CONCLUSION: SL could reduce the levels of TNF-alpha, hyper-leptinemia and hyperinsulinemia, antagonize insulin resistance, fortify insulin sensitivity, readjust lipodystrophy and maladjustment of glycometabolism, enhance antioxidation,and improve functions of liver and kidney in T2DR-IR.

Animals↗

PubMed2003

IL-8 directly enhanced endothelial cell survival, proliferation, and matrix metalloproteinases production and regulated angiogenesis.

IL-8, a member of the chemokine family, has been shown to play an important role in tumor growth, angiogenesis, and metastasis. The objective of this study was to determine the mechanism of IL-8-mediated angiogenesis. We examined the direct role of IL-8 in angiogenesis by examining IL-8 receptor expression on endothelial cells and their proliferation, survival, and matrix metalloproteinases (MMPs) production. We demonstrate that HUVEC and human dermal microvascular endothelial cells constitutively express CXCR1 and CXCR2 mRNA and protein. Recombinant human IL-8 induced endothelial cell proliferation and capillary tube organization while neutralization of IL-8 by anti-IL-8 Ab blocks IL-8-mediated capillary tube organization. Incubation of endothelial cells with IL-8 inhibited endothelial cell apoptosis and enhanced antiapoptotic gene expression. Endothelial cells incubated with IL-8 had higher levels of Bcl-x(L):Bcl-x(S) and Bcl-2:Bax ratios. Furthermore, incubation of endothelial cells with IL-8 up-regulated MMP-2 and MMP-9 production and mRNA expression. Our data suggest that IL-8 directly enhanced endothelial cell proliferation, survival, and MMP expression in CXCR1- and CXCR2-expressing endothelial cells and regulated angiogenesis.

Apoptosis↗

PubMed2003

Expression of CXCR1 and CXCR2 receptors in malignant melanoma with different metastatic potential and their role in interleukin-8 (CXCL-8)-mediated modulation of metastatic phenotype.

In the present study, we examined the autocrine/paracrine role of IL-8 in melanoma growth and metastasis by analyzing the expression and functional significance of IL-8 receptors, CXCR1 and CXCR2 in human malignant melanoma cells with different metastatic potential. CXCR1 and CXCR2 mRNA and protein levels were analyzed by reverse trannscriptase-based polymerase chain reaction, immunohistochemistry, immunoprecipitation, flow cytometry and ligand binding assay in melanoma cells in vitro and xenografted in nude mice. Melanoma cells constitutively expressed CXCR1 and CXCR2 mRNA and protein. Highly metastatic A375SM cells expressed higher levels of CXCR1 and CXCR2 mRNA and protein in vitro and in vivo as compared to low metastatic A375P and non-metastatic SBC-2 melanoma cells. Treatment of SBC-2 and A375P cells with exogenously added recombinant IL-8 significantly enhanced their proliferation and invasive potential. Further neutralizing antibodies to CXCR1 and CXCR2 inhibited proliferation and invasive potential of unstimulated and IL-8-stimulated A375P cells. In summary, the data suggest that constitutive expression of CXCR1 and CXCR2 play an important role regulating the IL-8-mediated metastatic phenotype in human malignant melanoma cells.

Animals↗