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Biomedical subjects

D Nie

Publications and source records attributed to D Nie.

At least 19 recordsLinked to original sources
PubMed2002

Cyclooxygenase, lipoxygenase and tumor angiogenesis.

Arachidonic acid metabolism through cyclooxygenase (COX) and lipoxygenase (LOX) pathways generates various biologically active lipids that play important roles in inflammation, thrombosis and tumor progression. Angiogenesis, the formation of new capillary vessels from preexisting ones, underpins a number of physiological processes and participates in the development of several pathological conditions such as arthritis, cancer and various eye diseases. The formation of new capillary vessels is a multistep process that involves endothelial cell proliferation, migration and tube formation. In the present review, we survey the literature on the regulation of angiogenesis by arachidonate metabolites, especially those from the COX and 12-LOX pathways in the context of tumor growth, and put forward some unanswered but important questions for future studies.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2001

Role of eicosanoids in prostate cancer progression.

Metabolism of arachidonic acid through cyclooxygenase, lipoxygenase, or P450 epoxygenase pathways leads to the formation of various bioactive eicosanoids. In this review, we discuss alterations in expression pattern of eicosanoid-generating enzymes found during prostate tumor progression and expound upon their involvement in tumor cell proliferation, apoptosis, motility, and tumor angiogenesis. The expression of cyclooxygenase-2, 12-lipoxygenase, and 15-lipoxygenase-1 are up-regulated during prostate cancer progression. It has been demonstrated that inhibitors of cyclooxygenase-2, 5-lipoxygenase and 12-lipoxygenase cause tumor cell apoptosis, reduce tumor cell motility and invasiveness, or decrease tumor angiogenesis and growth. The eicosanoid product of 12-lipoxygenase, 12(S)-hydroeicosatetraenoic acid, is found to activate Erkl/2 kinases in LNCaP cells and PKCalpha in rat prostate AT2.1 tumor cells. Overexpression of 12-lipoxygenase and 15-lipoxygenase-1 in prostate cancer cells stimulate prostate tumor angiogenesis and growth, suggesting a facilitative role for 12-lipoxygenase and 15-lipoxygenase-1 in prostate tumor progression. The expression of 15-lipoxygenase-2 is found frequently to be lost during the initiation and progression of prostate tumors. 15(S)-hydroxyeicosatetraenoic acid, the product of 15-lipoxygenase-2, inhibits proliferation and causes apoptosis in human prostate cancer cells, suggesting an inhibitory role for 15-lipoxygenase-2 in prostate tumor progression. The regulation of prostate cancer progression by eicosanoids, in either positive or negative ways, provides an exciting possibility for management of this disease.

Apoptosis↗
PubMed2001

[Changes in the activity of platelet L-arginine/nitric oxide pathway in hypercholesterolemia patients].

OBJECTIVE: To investigate the changes of the platelet L-arginine (L-Arg)/nitric oxide (NO) pathway in hypercholesterolemia patients. METHODS: The platelet NO production in 21 hypercholesterolemia (HC) patients and 26 normal individuals was assayed by spectrum, the NOS activity and the transportation of L-Arg were determined by (3)H-labelled L-Arg. RESULTS: The NO production in hypercholesterolemic platelets [(24.06 +/- 3.70) nmol/10(8) platelets] was decreased significantly as compared with normal controls [(28.39 +/- 4.45) nmol/10(8) platelets] (P < 0.01), and so did the NOS activity [(1.46 +/- 0.47) pmol/10(8) platelets] vs (1.81 +/- 0.50) pmol/10(8) platelets]. The transportation of L-Arg by hypercholesterolemia platelets also decreased significantly than that by normal controls. The Vmax in the former [(46.84 +/- 3.39) pmol x (10(7) platelets)(-1) x min(-1)] was significantly lower than that in the latter [(53.89 +/- 3.45) pmol x (10(7) platelets)(-1) x min(-1)]. There was no difference between the two groups in K(d) (P > 0.05). CONCLUSIONS: The activity of the L-arg/NO pathway in hypercholesterolemia platelets is decreased significantly as compared with normal controls, implying that it is probably one of the reasons for the hyperactivity of hypercholesterolemia platelets.

Adult↗
PubMed2000

Eicosanoid 12(S)-HETE activates phosphatidylinositol 3-kinase.

The arachidonic acid metabolite of 12 lipoxygenase, 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE) promotes metastatic behavior of tumor cells. In this study we set out to identify 12(S)-HETE signaling pathways, and their contribution to cellular functions in A431 epidermoid carcinoma. (1) 12(S)-HETE stimulated phosphotyrosine associated PI3 kinase activity. (2) 12(S)-HETE stimulated ERK1/2 in a PI3 kinase dependent manner. (3) PI3 kinase affected the 12(S)-HETE stimulated Raf/MEK/ERK cascade at the level of MEK. (4) 12(S)-HETE stimulated ERK1/2 via PKCzeta. (5) 12(S)-HETE stimulated cell migration on laminin, which was eliminated by PI3 kinase and cPKC inhibitors, but it was unaffected by inhibition of ERK1/2.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed2000

Expression, subcellular localization and putative function of platelet-type 12-lipoxygenase in human prostate cancer cell lines of different metastatic potential.

The involvement of 12-lipoxygenase (12-LOX) expression and function in tumor metastasis has been demonstrated in several murine tumor cell lines. In addition, 12-LOX expression was detected in human prostatic tumors and correlated to the clinical stage of disease. Here we provide data that human prostate cancer cell lines express the platelet-type isoform of 12-LOX at both the mRNA and protein levels, and immunohistochemistry revealed 12-LOX expression in human prostate tumors. The enzyme was localized to the plasma membrane, cytoplasmic organelles and nucleus in non-metastatic cells (PC-3 nm) and to the cytoskeleton and nucleus in metastatic cells (DU-145). After orthotopic/intraprostatic injection of tumor cells into SCID mice, the metastatic prostate carcinoma cells (DU-145) expressed 12-LOX at a significantly higher level compared with the non-metastatic counterparts, PC-3nm. The functional involvement of 12-LOX in the metastatic process was demonstrated when DU-145 cells were pretreated in vitro with the 12-LOX inhibitors N-benzyl-N-hydroxy-5-phenylpentamide (BHPP) or baicalein, the use of which significantly inhibited lung colonization. These data suggest a potential involvement of 12-LOX in the progression of human prostate cancer.

Animals↗
PubMed2000

Eicosanoid regulation of angiogenesis: role of endothelial arachidonate 12-lipoxygenase.

Angiogenesis, the formation of new capillaries from preexisting blood vessels, is a multistep, highly orchestrated process involving vessel sprouting, endothelial cell migration, proliferation, tube differentiation, and survival. Eicosanoids, arachidonic acid (AA)-derived metabolites, have potent biologic activities on vascular endothelial cells. Endothelial cells can synthesize various eicosanoids, including the 12-lipoxygenase (LOX) product 12(S)-hydroxyeicosatetraenoic acid (HETE). Here we demonstrate that endogenous 12-LOX is involved in endothelial cell angiogenic responses. First, the 12-LOX inhibitor, N-benzyl-N-hydroxy-5-phenylpentanamide (BHPP), reduced endothelial cell proliferation stimulated either by basic fibroblast growth factor (bFGF) or by vascular endothelial growth factor (VEGF). Second, 12-LOX inhibitors blocked VEGF-induced endothelial cell migration, and this blockage could be partially reversed by the addition of 12(S)-HETE. Third, pretreatment of an angiogenic endothelial cell line, RV-ECT, with BHPP significantly inhibited the formation of tubelike/cordlike structures within Matrigel. Fourth, overexpression of 12-LOX in the CD4 endothelial cell line significantly stimulated cell migration and tube differentiation. In agreement with the critical role of 12-LOX in endothelial cell angiogenic responses in vitro, the 12-LOX inhibitor BHPP significantly reduced bFGF-induced angiogenesis in vivo using a Matrigel implantation bioassay. These findings demonstrate that AA metabolism in endothelial cells, especially the 12-LOX pathway, plays a critical role in angiogenesis.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed2000

Identification of 12-lipoxygenase interaction with cellular proteins by yeast two-hybrid screening.

The platelet isoform of 12-lipoxygenase (12-LOX) is expressed in a variety of human tumors. 12-LOX metabolizes arachidonic acid to 12(S)-hydroxyeicosateraenoic acid (12(S)-HETE), which induces a number of cellular responses associated with tumor progression and metastasis. Little is known about 12-LOX regulation and no direct regulators of 12-LOX activity have been identified. To identify potential regulators of 12-LOX, we isolated cDNAs encoding 12-LOX interacting proteins using the yeast two-hybrid system. We screened a yeast two-hybrid interaction library from human epidermoid carcinoma A431 cells and identified four cellular proteins that interact specifically with 12-LOX. We identified type II keratin 5, lamin A, the cytoplasmic domain of integrin beta4 subunit and a phosphoprotein C8FW as 12-LOX interacting proteins. Here, we demonstrated that keratin 5, a 58 kD protein required for formation of 8 nm intermediate filaments, binds to 12-LOX in human tumor cells and may contribute to the regulated trafficking of 12-LOX. We also showed that lamin A binds 12-LOX in human tumor cells. These proteins provide the first candidate regulators of 12-LOX.

Antigens, CD↗
PubMed2000

Thromboxane A(2) regulation of endothelial cell migration, angiogenesis, and tumor metastasis.

Prostaglandin endoperoxide H synthases and their arachidonate products have been implicated in modulating angiogenesis during tumor growth and chronic inflammation. Here we report the involvement of thromboxane A(2), a downstream metabolite of prostaglandin H synthase, in angiogenesis. A TXA(2) mimetic, U46619, stimulated endothelial cell migration. Angiogenic basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF) increased TXA(2) synthesis in endothelial cells three- to fivefold. Inhibition of TXA(2) synthesis with furegrelate or CI reduced HUVEC migration stimulated by VEGF or bFGF. A TXA(2) receptor antagonist, SQ29,548, inhibited VEGF- or bFGF-stimulated endothelial cell migration. In vivo, CI inhibited bFGF-induced angiogenesis. Finally, development of lung metastasis in C57Bl/6J mice intravenously injected with Lewis lung carcinoma or B16a cells was significantly inhibited by thromboxane synthase inhibitors, CI or furegrelate sodium. Our data demonstrate the involvement of TXA(2) in angiogenesis and development of tumor metastasis.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2000

Eicosanoid regulation of angiogenesis in human prostate carcinoma and its therapeutic implications.

Cancer of the prostate is the most commonly diagnosed cancer in America. There are several lines of evidence implicating the involvement of arachidonate 12-lipoxygenase, an enzyme metabolizing arachidonic acid to form 12(S)-hydroxyeicosatetraenoic acid (HETE), in prostate cancer progression. First, as prostate cancer reaches a more advanced stage, the level of 12-lipoxygenase expression is increased. Second, overexpression of 12-lipoxygenase in human prostate cancer cells stimulates angiogenesis and tumor growth. Third, an inhibitor of 12-lipoxygenase has been found effective against metastatic prostate tumor growth, and the inhibition of 12-lipoxygenase is related with the reduction of tumor angiogenesis. Collectively, these studies suggest that 12-lipoxygenase regulates tumor angiogenesis in prostate cancer and that inhibition of 12-lipoxygenase is a novel therapeutic approach for the treatment of prostate cancers.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed2000

[Influence of pravastatin on expression of platelet CD(62P) and CD(41) in patients with hypercholesterolemia in vitro and in vivo].

OBJECTIVE: To study in vitro and in vivo effect of hypercholesterolemia (HC) on expression of platelet CD(62P) and CD(41) and their changes after treatment with pravastatin. METHODS: Twenty patients with HC were given 10 - 20 mg/d pravastatin orally for 4 - 8 weeks. Changes of blood cholesterol and expression of platelet CD(62P) and CD(41) were detected by flow cytometry. RESULTS: After 4 and 8 weeks' treatment, blood cholesterol level and platelet aggregation function decreased. The expression of CD(62P) average fluorescence intensity decreased from 31.8 +/- 7.8 to 27.2 +/- 6.9 and 26.8 +/- 4.9; CD(62P) (%) from (31.3 +/- 9.3)% to (26.4 +/- 7.4)% and (25.3 +/- 9.1)% (P < 0.05); CD(41) from 483.2 +/- 263.9 to 348.1 +/- 192.4 and 306.8 +/- 128.0 (P < 0.05), respectively. Similar results were obtained in vitro study. CONCLUSION: Improvement of platelet function and expressions of CD(62P) and CD(41) in HC patients after prevastatin treatment may be resulted from enhancing arteriosclerosis regression. It suggested from the in vitro result that pravastatin might play a direct effect on platelet function.

Adult↗
PubMed1999

The beta4 integrin subunit rescues A431 cells from apoptosis through a PI3K/Akt kinase signaling pathway.

To study whether alpha6beta4 integrin regulates apoptosis, human A431 cells were plated on bacteria plates in the presence or absence of mAb beta4. In the absence of mAb beta4, A431 cells demonstrated morphological characteristics of apoptosis by 24 h and most cells died by 48 h. In contrast, in the presence of mAb beta4, cells remained viable, and at the end of 48 h, 70-80% of cells survived. Treatment of A431 cells with mAb beta4 resulted in tyrosine phosphorylation of the p85 subunit of PI3 kinase; PI3 kinase activity increased within 15 min and peaked at 60 min. Stimulation of beta4 in A431 cells resulted in a time-dependent phosphorylation of Akt with a concomitant and parallel phosphorylation of Bad. Inactivation of PI3 kinase with inhibitors blocked the anti-apoptotic effect induced by mAb beta4. These are the first results to suggest that ligation of alpha6beta4 integrin protects cells from apoptosis through a PI3K/Akt kinase signaling pathway.

Antigens, CD↗
PubMed1998

Platelet-type 12-lipoxygenase in a human prostate carcinoma stimulates angiogenesis and tumor growth.

Previously, we found a positive correlation between the expression of platelet-type 12-lipoxygenase (12-LOX) and the progression of human prostate adenocarcinoma (PCa; Gao et al., Urology, 46: 227-237, 1995). To determine the role of 12-LOX in PCa progression, we generated stable 12-LOX-transfected PC3 cells, which synthesize high levels of 12-LOX protein and 12(S)-hydroxyeicosatetraenoic acid metabolite. In vitro, 12-LOX-transfected PC3 cells demonstrated a proliferation rate similar to neo controls. However, following s.c. injection into athymic nude mice, 12-LOX-transfected PC3 cells formed larger tumors than did the controls. Decreased necrosis and increased vascularization were observed in the tumors from 12-LOX-transfected PC3 cells. Both endothelial cell migration and Matrigel implantation assays indicate that 12-LOX-transfected PC3 cells were more angiogenic than their neo controls. These data indicate that 12-LOX stimulates human PCa tumor growth by a novel angiogenic mechanism.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1998

Inhibition of terminal differentiation and matrix calcification in cultured avian growth plate chondrocytes by Rous sarcoma virus transformation.

Endochondral bone formation involves the progression of epiphyseal growth plate chondrocytes through a sequence of developmental stages which include proliferation, differentiation, hypertrophy, and matrix calcification. To study this highly coordinated process, we infected growth plate chondrocytes with Rous sarcoma virus (RSV) and studied the effects of RSV transformation on cell proliferation, differentiation, matrix synthesis, and mineralization. The RSV-transformed chondrocytes exhibited a distinct bipolar, fibroblast-like morphology, while the mock-infected chondrocytes had a typical polygonal morphology. The RSV-transformed chondrocytes actively synthesized extracellular matrix proteins consisting mainly of type I collagen and fibronectin. RSV-transformed cells produced much less type X collagen than was produced by mock-transformed cells. There also was a significant reduction of proteoglycan levels secreted in both the cell-matrix layer and culture media from RSV-transformed chondrocytes. RSV-transformed chondrocytes expressed two- to- threefold more matrix metalloproteinase, while expressing only one-half to one-third of the alkaline phosphatase activity of mock infected cells. Finally, RSV-transformed chondrocytes failed to calcify the extracellular matrix, while mock-transformed cells deposited high levels of calcium and phosphate into their extracellular matrix. These results collectively indicate that RSV transformation disrupts the preprogrammed differentiation pattern of growth plate chondrocytes and inhibit chondrocyte terminal differentiation and mineralization. They also suggest that the expression of extracellular matrix proteins, type II and type X collagens, and the cartilage proteoglycans are important for chondrocyte terminal differentiation and matrix calcification.

Alkaline Phosphatase↗
PubMed1998

Induction and characterization of metallothionein in chicken epiphyseal growth plate cartilage chondrocytes.

Following exposure to cadmium or zinc, chickens were sacrificed and the liver, kidney, and bone epiphyseal growth plates harvested. When cytosolic extracts of the growth plate cartilage were fractionated by gel filtration chromatography, a protein with high metal-binding capacity and low ultraviolet (UV) absorbance eluted in the same position as liver metallothionein (MT) and a MT standard. Cd or Zn treatment resulted in a 25-fold or 5-fold induction in growth plate MT, respectively. In liver the greatest level of MT induction was seen with short-term Cd exposures. In contrast, MT levels in the growth plate increased as the duration of Cd exposure increased. Induction of MT in growth plate chondrocyte cell cultures was observed for media Cd concentrations of > or = 0.1 microM and Zn concentrations of > or = 100 microM. Basal and inducible levels of MT declined through the culture period and were lowest in the terminally differentiated mineralized late stages of the culture. Alkaline phosphatase activity was also lowest in the late-stage cultures, while total cellular protein increased throughout the culture period. Treatment of chondrocytes with Zn prior to Cd exposure resulted in a protective induction of MT. Pre-treatment of chondrocytes with dexamethasone resulted in suppressed synthesis of MT upon Cd exposure and greater Cd toxicity. Both Cd and Zn resulted in significantly increased levels of MT mRNA in chondrocyte cell cultures. Dexamethasone treatment resulted in an approximate 2- to 3-fold increase in MT mRNA. This is contrary to the finding that MT protein levels were decreased by dexamethasone. The findings suggest that an increased rate of MT degradation in dexamethasone-treated and late-stage chondrocyte cultures may be associated with the terminally differentiated phenotype.

Animals↗