Biomedical subjects

K Xie

Publications and source records attributed to K Xie.

At least 37 records · Page 2Linked to original sources

PubMed2000

Differential regulation of type IV collagenases and metalloelastase in murine macrophages by the synthetic bacterial lipopeptide JBT 3002.

We determined whether the expression of matrix metalloproteinases (MMP) and tissue inhibitors of MMPs (TIMP) in murine macrophages is regulated by the novel synthetic bacterial lipopeptide JBT 3002. Multilamellar liposomes (MLV) encapsulating JBT 3002 (MLV-JBT 3002) stimulated the production of 72-kDa and 92-kDa (gelatinase A and B) type IV collagenase and inhibited the production of murine metalloelastase (MME) in a dose-dependent manner in murine peritoneal macrophages. MLV-JBT 3002 also induced production of TIMP-1. MLV-JBT 3002 did not induce collagenase production in tumor cells. Priming murine macrophages with interferon-gamma (IFN-gamma) inhibited JBT 3002-stimulated production of both MMP-9 and MMP-2 and further inhibited production of MME by a mechanism involving nitric oxide (NO). This conclusion is based on data showing that IFN-gamma failed to inhibit production of MMP in the presence of L-methyl arginine or in macrophages from inducible nitric oxide synthase knockout mice. These data suggest that JBT 3002 differentially regulates the production of various MMPs and TIMP in macrophages.

Adjuvants, Immunologic↗

PubMed2000

Molecular regulation of constitutive expression of interleukin-8 in human pancreatic adenocarcinoma.

Recent studies have shown that interleukin-8 (IL-8) plays an important role in the growth and metastasis of human pancreatic cancer. In the present study, we determined the molecular regulation of constitutive IL-8 expression in human pancreatic cancer cells. Various human pancreatic cancer cell lines were incubated in vitro. Sixty-seven percent of the cell lines constitutively secreted high levels of IL-8, as determined using enzyme-linked immunosorbent assay. Consistently, these cells constitutively expressed high levels of IL-8 mRNA, as determined using Northern blot analysis. To determine the mechanisms of the high steady-state levels of IL-8 mRNA, the IL-8 half-life and transcription rate were measured. There was no significant difference in IL-8 half-life between cells expressing high and low levels of IL-8. However, higher transcription rates and increased IL-8 promoter activity were observed in the cells constitutively expressing high levels of IL-8. Detailed IL-8 promoter analysis using deletion mutation revealed that the region from -85 to -133 bp was essential for the constitutive IL-8 promoter activity. Also, point-mutation analysis indicated that mutation of NF-kappaB, AP-1, or NF-IL-6 binding sites significantly reduced or eliminated the constitutive IL-8 promoter activity. Consistent with the constitutive IL-8 transcription activity, high levels of constitutive NF-kappaB and AP-1 activity were detected in the cells overexpressing IL-8, as determined using electrophoretic mobility shift assay. In addition, transfection of a dominant-negative I-kappaBalpha expression vector (I-kappaBalphaM) inhibited constitutive NF-kappaB activity and IL-8 expression in pancreatic cancer cells. Collectively, our data demonstrated that constitutive NF-kappaB and AP-1 activation contributes to the overexpression of IL-8, which in turn plays an important role in tumor angiogenesis and contributes to the aggressive biology of human pancreatic cancer.

Adenocarcinoma↗

PubMed2000

Regulation of interleukin-8 expression by cellular pH in human pancreatic adenocarcinoma cells.

The role of cellular pH in the expression and regulation of interleukin-8 (IL-8) in human tumor cell lines was determined. Transient exposure to pH ranging from 7.4 to 6.7 induced pH-dependent expression of IL-8 at both the mRNA and protein levels in three different human tumor cell lines, including COLO357 pancreatic adenocarcinoma cells, SW620 colon adenocarcinoma cells, and PC3 prostate adenocarcinoma cells. Investigation of the mechanisms of IL-8 induction in response to acidosis was carried out using the COLO357 human pancreatic cancer cell line. The increased steady-state level of mRNA correlated with an increased transcription rate and stability of IL-8 transcripts. Further experiments indicated that mild acidosis activated the transcription factors NF-kappaB and AP-1 and that the cooperation of these two factors appeared to be essential to the transactivation of the IL-8 gene. Our data demonstrated that low tumor pH contributes to the enhanced expression of IL-8 and plays an important role in tumor progression.

Adenocarcinoma↗

PubMed2000

Experimental animal models of pancreatic cancer (review).

Pancreatic adenocarcinoma is currently the fifth leading cause of cancer-related death in the United States and is largely refractory to conventional therapies. The average survival from diagnosis to death is 4-6 months. The major cause of death is rapid development of metastasis involving the lymph nodes, liver, lungs, or peritoneum. To understand its etiology and eventually to make prevention possible and effective, appropriate carcinogenesis models will certainly help shed more light on the process of pancreatic carcinogenesis and help us understand the effects of environmental and genetic elements on pancreatic cancer development. The development of new treatment strategies to control cancer metastasis is of immediate urgency. Fulfillment of this difficult task relies on our knowledge of the cellular and molecular biology of pancreatic cancer metastasis, and the use of relevant animal models will certainly help define each aspect of this complicated process.

Adenocarcinoma↗

PubMed2000

[Clinical use of central electronic monitoring system].

OBJECTIVE: To evaluate the effects of central electronic monitoring system (CEMS). METHODS: A total of 1,216 patients with > or = 37 weeks of gestation assigned as monitoring group, were performed central electronic monitoring during labor from Nov. 1997 to Mar. 1998. A total of 1,137 patients with same gestational age assigned as control group, were monitored by using intermittent auscultation during labor from Nov. 1996 to Mar. 1997. The rate of fetal distress, neonatal asphyxia, cesarean section, and using of forceps or vacuum extractor in the 2 groups were compared. RESULTS: Patients in the monitoring group had a higher fetal distress rate (12.8%) than that of the control group (9.8%, P < 0.05), but a significantly lower neonatal asphyxia rate (2.3%) than that of the control group (4.8%, P < 0.01). There were no significant differences in the overall cesarean rate, cesarean rate for fetal distress, overall use rate of forceps or vacuum extractor delivery, and vaginal operative delivery rate for suspected fetal distress between the two groups (P > 0.05). CONCLUSION: Quality for obstetric care was significantly improved by application of central electronic monitoring for labor management, it didn't increase the cesarean section rate and vaginal operative delivery rate, but decreased the neonatal asphyxia rate.

Asphyxia Neonatorum↗

PubMed1999

Hypoxia-induced elevation in interleukin-8 expression by human ovarian carcinoma cells.

The expression level of interleukin-8 (IL-8) directly correlates with the progression of human ovarian carcinomas implanted into the peritoneal cavity of nude mice, but the mechanism of induction is unknown. Because hypoxia induces expression of vascular endothelial growth factor/vascular permeability factor, which, like IL-8, is an angiogenesis-regulating molecule, we determined whether hypoxic conditions could regulate the expression of IL-8. Surgical specimens of human ovarian carcinomas were prepared for immunohistochemical and in situ hybridization analysis. Elevated levels of IL-8 mRNA and protein were found in tumor cells adjacent to necrotic zones. In vitro exposure of human ovarian carcinoma cell lines SKOV3 i.p.1 and Hey-A8 to hypoxia resulted in a time-dependent increase in steady-state levels of IL-8 mRNA (Northern blot) and in increased production and secretion of IL-8 protein (ELISA). Hypoxia-mediated transient induction of IL-8 expression could be ascribed to both an increase in IL-8 mRNA stability and transcriptional activation of the IL-8 gene promoter. Detailed functional analysis of the IL-8 promoter revealed that the sequence between -133 and -98 bp relative to the transcription initiation site was primarily responsible for IL-8 gene transcriptional activation by hypoxia. Point-mutated luciferase reporter studies indicated that AP-1 and NF-kappaB-like factor binding elements were mainly responsible for hypoxia-induced increase in IL-8 gene expression in human ovarian cancer cells, and that IL-8 transcription activation by hypoxia required the cooperation of NF-kappaB and AP-1 binding sites.

Binding, Competitive↗

PubMed1999

Direct correlation between nitric oxide synthase II inducibility and metastatic ability of UV-2237 murine fibrosarcoma cells carrying mutant p53.

The relationship between nitric oxide synthase II (NOS II) inducibility and the metastatic ability of UV-2237 murine fibrosarcoma cells was determined. Highly metastatic cells survived to produce numerous lung metastases after i.v. injection in syngeneic C3H/HeN mice, whereas poorly metastatic cells did not. Highly metastatic clones exhibited higher levels of NOS II than did poorly metastatic clones in response to interleukin 1alpha and IFN-gamma stimulation. Furthermore, both poorly and highly metastatic clones contained an identical p53 mutation. Overexpression of NOS II in a highly metastatic clone by transfection with NOS II gene retarded tumor growth and completely suppressed metastasis. Our data indicate that a low to moderate level of NOS II expression directly correlates with metastatic ability of UV-2237 fibrosarcoma cells carrying mutant p53 and that a high level of nitric oxide production suppresses tumor growth and metastasis.

Animals↗

PubMed1999

Regulation of vascular endothelial growth factor expression in human colon cancer by interleukin-1beta.

Expression of vascular endothelial growth factor (VEGF), an important angiogenic factor in colon cancer, is tightly regulated by factors in the microenvironment. However, specific factors indigenous to the organ microenvironment of colon cancer growth that regulate VEGF expression in human colon cancer are not well defined. We investigated interleukin-1beta (IL-1beta) induction of VEGF expression in colon cancer cells and the mechanism by which this occurs. HT29 human colon cancer cells were treated with IL-1beta for various periods. Induction of VEGF mRNA by IL-1beta peaked at 24 h (> fivefold) and returned to baseline by 48 h. SW620 human colon cancer cells also reached a peak induction of VEGF mRNA 24 h after treatment with IL-1beta. VEGF was induced at a dose range between 1 and 20 ng ml(-1) of IL-1beta. IL-1beta induction of VEGF was also confirmed at the protein level. To examine the mechanism for VEGF induction by IL-1beta, we transiently transfected VEGF promoter-reporter constructs into HT29 cells. IL-1beta increased the activity of the VEGF promoter-reporter construct. Pretreatment of HT29 cells with dactinomycin abrogated the induction of VEGF mRNA by IL-1beta. The half-life of VEGF mRNA was not prolonged by treatment with IL-1beta. These findings suggest that IL-1beta regulates VEGF expression in human colon cancer cells by increasing transcription of the VEGF gene.

Colonic Neoplasms↗

PubMed1999

Cooperation between transcription factor AP-1 and NF-kappaB in the induction of interleukin-8 in human pancreatic adenocarcinoma cells by hypoxia.

The expression of interleukin-8 (IL-8) has been shown to play an important role in the growth and metastasis of human pancreatic cancer. In the present study, we investigated the regulation of IL-8 gene expression by hypoxic environments. Exposure of the human pancreatic cancer cells COLO357 and FG to hypoxia in culture resulted in a time-dependent increase in steady-state levels of IL-8 mRNA and IL-8 protein secretion. The induction of IL-8 expression was correlated with transcriptional activation of the IL-8 gene. Deletion and point mutation analyses of the IL-8 promoter revealed that both AP-1 and NF-kappaB binding sites were necessary for IL-8 induction by hypoxia. Consistently, hypoxia induced both AP-1 and NF-kappaB activity. These data suggest that hypoxic environments upregulate the IL-8 gene via cooperation of NF-kappaB and AP-1 and contribute to the progression and metastasis of human pancreatic cancer.

Adenocarcinoma↗

PubMed1999

Constitutive and inducible interleukin 8 expression by hypoxia and acidosis renders human pancreatic cancer cells more tumorigenic and metastatic.

The role and regulation of interleukin 8 (IL-8) in the growth and metastasis of SG, FG, and L3.3 variants derived from COLO 357 human pancreatic cancer cells were determined. After orthotopic implantation in the pancreas of nude mice, SG cells produced the smallest tumors, whereas L3.3 cells produced the largest tumors. SG cells produced no liver metastasis, whereas FG cells produced numerous liver metastases, and L3.3 cells produced more and larger liver metastases. In vitro analysis of IL-8 expression indicated that SG cells expressed the lowest level of IL-8 gene expression as determined by both Northern blot analysis and ELISA, whereas L3.3 cells expressed the highest level of IL-8. Immunohistochemical analysis of tumor lesions indicated that IL-8 overexpression was predominant in the regions surrounding necrotic areas, where cells were exposed to low oxygen tension (hypoxia) and acidic pH. In vitro treatment of FG tumor cells with hypoxia or acidosis led to an increased expression of IL-8. To directly determine the role of IL-8 in the growth and metastasis of pancreatic cancer, FG cells were transfected with IL-8 sense or antisense oligonucleotide expression vectors. The neo-resistance gene-transfected FG cells were used as controls. Decreased IL-8 expression after transfection with IL-8 antisense oligonucleotide expression vector retarded the growth of FG cells in mice after intrapancreatic implantation, which correlated with decreased tumor angiogenesis. Our data demonstrated that hypoxia and acidosis contribute to the overexpression of IL-8, which in turn plays an important role in tumor angiogenesis and contributes significantly to the aggressive biology of human pancreatic cancer.

Acidosis↗

PubMed1998

Therapy of human ovarian cancer by transfection with the murine interferon beta gene: role of macrophage-inducible nitric oxide synthase.

The purpose of this study was to determine whether the local sustained production of murine interferon beta (mIFN-beta) could inhibit the growth of human ovarian cancer cells in the peritoneal cavity of nude mice. Human ovarian tumor Hey-A8 cells transfected with mIFN-beta (Hey-beta) or a control neomycin resistance vector (Hey-Neo) grew well in culture. Tumor cells were injected into the peritoneal cavity or under the subcutis of nuce mice. Parental (wild-type) or control transfected cells produced large tumors, whereas mIFN-beta-transfected cells did not produce any tumors. The IFN-beta-transfected cells prevented the outgrowth of bystander parental, control-transfected cells, and another human ovarian tumor cell line, SKOV3i.p.1, in the peritoneal cavity of nude mice. The IFN-beta-transfected tumor cells stimulated a high level of nitric oxide (NO) production in murine macrophages under both in vitro and in vivo conditions, and only the NO-producing macrophages exhibited antitumor activity. Collectively, these results demonstrate that the local production of IFN-beta can inhibit the in vivo growth of human ovarian cancer cells by upregulating the expression of the inducible nitric oxide synthase (iNOS) gene in host macrophages.

Animals↗

PubMed1998

Regulation of vascular endothelial growth factor expression in human colon cancer by insulin-like growth factor-I.

We investigated the role of insulin-like growth factor (IGF)-I and IGF-binding proteins (IGFBPs) in the regulation of vascular endothelial growth factor (VEGF) expression in colon cancer cells and the mechanism by which this regulation occurs. HT29 human colon cancer cells were treated with IGF-I for various time periods. VEGF mRNA expression increased within 2 h and peaked at 24 h. SW620 colon cancer cells exhibited a peak induction of VEGF mRNA 8 h after IGF-I treatment. IGF-I induction of VEGF was confirmed at the protein level. In experiments using transient transfection of VEGF promoter-reporter constructs into HT29 cells, IGF-I increased the activity of the VEGF promoter, and pretreatment of HT29 cells with dactinomycin abrogated the induction of VEGF mRNA by IGF-I. The half-life of VEGF mRNA was not prolonged by treatment with IGF-I. Blocking the activity of IGFBP-4 did not significantly modulate the effect of IGF-I induction of VEGF mRNA in HT29 cells. Treating cells with des-(1-3)-IGF-I (an active derivative of IGF-I that does not bind to binding proteins) had effects on VEGF mRNA expression that were similar to those of IGF-I. These findings suggest that IGF-I regulates VEGF expression in human colon cancer cells by induction of transcription of the VEGF gene. IGFBPs do not significantly affect IGF-I induction of VEGF.

Colonic Neoplasms↗

PubMed1998

Procathepsin-L, a proteinase that cleaves human C3 (the third component of complement), confers high tumorigenic and metastatic properties to human melanoma cells.

We previously demonstrated that highly metastatic human melanoma cells secrete a 41 kDa proteinase that cleaves C3, the third component of complement, and shares antigenic determinants with procathepsin-L. Thus, we herein transfected the nonmetastatic DX-3 melanoma cells with the procathepsin-L cDNA. Three clones expressing and secreting high levels of procathepsin-L were selected. Conditioned medium and whole cell extracts from these clones, but not from control cells, carried a high C3-cleaving activity. The transfected clones displayed up to 60% resistance to complement-mediated lysis. Overexpression of procathepsin-L in melanoma cells increased their tumorigenicity and switched their phenotype from nonmetastatic to highly metastatic cells. This is the first report that demonstrates that enforced expression of procathepsin-L by human melanoma cells arms them with the ability to inactivate complement-mediated lysis and contributes to tumor growth and metastasis.

Animals↗

PubMed1998

Suppression of tumorigenicity and metastasis of human renal carcinoma cells by infection with retroviral vectors harboring the murine inducible nitric oxide synthase gene.

The purpose of this study was to determine whether retrovirus-mediated transfer of the murine macrophage inducible nitric oxide synthase (iNOS) gene can inhibit tumorigenicity and metastasis of human renal cancer cells. Retroviral vectors encoding murine macrophage iNOS were constructed in the pLXSN retroviral vector with the iNOS gene under the control of a long terminal repeat promoter and a neomycin resistance gene under the control of an internal simian virus 40 promoter. Highly metastatic human renal carcinoma SN12PM6 cells were infected with control or iNOS retrovirus. Expression of iNOS was confirmed by Northern and Western blot analyses, and expression of the functional iNOS protein, i.e., production of nitric oxide (NO), was determined by measuring nitrite accumulation in culture supernatants. Noninfected or control cells produced large orthotopic tumors in the kidney of nude mice and a larger number of experimental lung metastases, whereas iNOS-infected cells produced small tumors in the kidneys and few to no lung metastases. The data indicate that the infection of human renal cancer cells by retroviruses harboring the murine iNOS gene can induce the production of high levels of NO, which is associated with autocytotoxicity, suppression of tumorigenicity, and abrogation of metastasis.

Animals↗

PubMed1998

Suppression of tumorigenicity and metastasis in murine UV-2237 fibrosarcoma cells by infection with a retroviral vector harboring the interferon-beta gene.

In this study, we endeavored to determine the effectiveness of interferon beta (IFNbeta) gene therapy against highly metastatic murine UV-2237m fibrosarcoma cells. UV-2237m cells were engineered to produce murine IFNbeta constitutively following infection by a retroviral vector harboring the murine IFNbeta gene. Parental (UV-2237m-P), control-vector-transduced (UV-2237m-Neo), and IFNbeta-transduced (UV-2237m-IFNbeta) cells were injected subcutaneously (s.c.) or intravenously (i.v.) into syngeneic mice. Parental and control-transduced cells produced rapidly growing tumors, whereas IFNbeta-transduced cells did not. The tumorigenicity of IFNbeta-sensitive or -resistant parental cells was significantly suppressed when they were injected s.c. together with IFNbeta-transduced cells. The IFNbeta-transduced cells did not inhibit growth of parental cells injected s.c. at a distant site. UV-2237m-IFNbeta cells produced s.c. tumors in nude, SCID/Beige, and natural killer(NK)-cell-compromised syngeneic mice. The IFNbeta-transduced cells were more sensitive to in vitro splenic cell-mediated lysis than were the parental or control-transduced cells. Pretreatment of C3H/HeN mice with the NK-cell-selective antiserum (anti-asialoGM1) partially abrogated the cytotoxic activity of the cells. Cytotoxic activity was not observed in mixed culture of UV-2237m-IFNbeta cells and splenic cells from SCID/Beige mice. Significant cytotoxicity against UV-2237m-IFNbeta cells was mediated by macrophages activated by either IFNgamma, lipopolysaccharide, or a combination of both. Our data led us to conclude that the constitutive expression of IFNbeta can suppress tumorigenicity and metastasis of UV-2237m cells, which is due, in part, to activation of host effector cells.

Animals↗

PubMed1998

Therapy of cancer metastasis by activation of the inducible nitric oxide synthase.

The process of cancer metastasis consists of multiple sequential and highly selective steps. The vast majority of tumor cells that enter the circulation die rapidly; only a few survive to produce metastases. This survival is not random. Metastases are clonal in origin and are produced by specialized subpopulations of cells that preexist in a heterogeneous primary tumor. Experimental studies concluded that metastatic cells survive in the circulation whereas nonmetastatic cells do not. In part, this difference is due to an inverse correlation between expression of endogenous inducible nitric oxide synthase (iNOS) and production of nitric oxide (NO) and metastatic potential. Direct evidence for the role of iNOS in metastasis has been provided by our data on transfection of highly metastatic murine K-1735 clone 4 (C4.P) cells which express low levels of iNOS, with a functional iNOS (C4.L8), inactive mutated iNOS (C4.S2), or neomycin resistance (C4.Neo) genes in medium containing 3 mM of the specific iNOS inhibitor NG-L-methyl arginine (NMA). C4.P, C4.Neo, and C4.S2 cells were highly metastatic, whereas C4.L8 cells were not. Moreover, C4.L8 cells produced slow-growing subcutaneous tumors in nude mice, whereas the other 3 cell lines produced fast-growing tumors. In vitro studies indicated that the expression of iNOS in C4.L8.5 cells was associated with either cytostasis or cytolysis via apoptosis, depending upon NO output. The tumor cells producing high levels of NO underwent autocytolysis and produced cytolysis of bystander cells under both in vitro and in vivo conditions. Multiple i.v. injections of liposomes containing a synthetic lipopeptide upregulated iNOS expression in murine M5076 reticulum sarcoma cells growing as hepatic metastases. The induction of iNOS was associated with the complete regression of the lesions. Transfection of interferon-beta suppressed tumor formation and eradicated metastases, which was apparently linked to iNOS expression and NO production in host cells such as macrophage. Besides mediating cell death, NO produced tumor suppression by regulating expression of genes related to metastasis, e.g., survival, invasion, and angiogenesis. Suppression of metastasis can be achieved through use of immunomodulators that induce iNOS expression in tumor lesions or by the direct delivery of the iNOS gene to tumor cells or host cells through liposome and/or viral vectors.

Animals↗

PubMed1998

[A primary study of transcranial magnetic stimulation (TMS)-induced muscle silent period(SP) in stroke patients with mild hemiparesis].

OBJECTIVE: To investigate the changes of muscle silent period (SP) induced by transcranial magnetic stimulation (TMS) and its value in the evaluation of motor function in patient with stroke. METHODS: 25 normals and 23 stroke patients with mild hemiparesis were involved in this study. A MES-10 magnetic stimulator and a 9 cm round coil were used to stimulate the brain at an intensity 50% above threshold for MEP with the subjects making sustained moderate contraction of the contralateral FDI. SP duration and interside ratio were measured and calculated and then compared between the two groups. RESULTS: Normal values of SP duration and interside ratio were 145 +/- 37 ms and 1.01 +/- 0.15 respectively. The SP duration on the paralytic side in stroke patients was 423 +/- 314 ms, significantly prolonged in comparison with that on the normal side (154 +/- 54 ms, P < 0.05) and that of normal value (P < 0.01). The interside SP ratio (paralytic/normal side) in stroke patients was 2.8 +/- 1.9, also significantly higher than the normal value (P < 0.01). CONCLUSION: SP might be a sensitive and valuable neurophysiological parameter in evaluation of the motor function of patients with central motor dysfunction.

Adult↗

PubMed1998

Mechanism of allyl chloride-induced cytoskeletal injury to nerve cells.

OBJECTIVE: To dissect the molecular mechanism of toxic neuropathy induced by allyl chloride (AC). METHODS: Fluorescence molecular probe (Fura-2/AM), electron probe X-ray microprobe analysis (EPMA) and biochemical methods were used to determine the concentrations of cytosolic free Ca2+, the contents of intracellular Ca2+ percentage, Ca(2+)-free calmodulin (CaM), the activity of Ca2+/CaM-dependent protein kinase II (Ca2+/CaM-PK II), and cytoskeletal protein synthesis in chicken embryo brain cells induced by AC. RESULTS: The contents of Ca2+ percentage, the concentrations of cytosolic free Ca2+, and the activities of Ca2+/CaM-PK II in the cells were increased significantly as AC was added (P < 0.01). However, the content of Ca(2+)-free CaM and the synthesis of cytoskeletal proteins were markedly decreased (P < 0.01). CONCLUSION: The results suggest that one of the mechanism of AC-induced cytoskeletal injury in vitro might be related to the elevation of intracellular Ca2+, activated CaM and Ca2+/CaM-PK II.

Allyl Compounds↗