Research Interests: Stem Cells, Flow Cytometry, Confocal Microscopy, Stem Cell, Immunocytochemistry, and 15 moreTransgenic Mice, Macular Degeneration, Biological Sciences, Hematopoietic Stem Cells, Mice, Animals, Bone marrow, Age related macular degeneration, Blood Vessels, Blood Vessel, Blood cells, Adult Stem Cell, Choroidal Neovascularization Industry, Hematopoietic Stem Cell, and Hematopoietic Stem Cell Transplantation
Research Interests:
Research Interests: Confocal Microscopy, Stem Cell, Nature, Transgenic Mice, Hematopoietic Stem Cells, and 11 moreIschemia, Mice, Animals, Retina, Green Fluorescent Protein, Clinical Sciences, Optometry and Ophthalmology, Endothelial cell, Public health systems and services research, Hematopoietic Stem Cell, and Hematopoietic Stem Cell Transplantation
Research Interests:
Research Interests:
Research Interests:
... Capillary Cell Proliferation and Migration Maria B. Grant, Sergio Caballero, David M. Bush, and Polyxenie E. Spoerri ... Their effects on migration were assessed using modified Boyden chambers. Seven Fn-f were tested on vascular cell... more
... Capillary Cell Proliferation and Migration Maria B. Grant, Sergio Caballero, David M. Bush, and Polyxenie E. Spoerri ... Their effects on migration were assessed using modified Boyden chambers. Seven Fn-f were tested on vascular cell migration and/or prolifer-ation. ...
Research Interests:
Research Interests: Technology, Human Embryonic Stem Cells, Human embryonic stem cell, Stem Cell Transplantation, Biological Sciences, and 18 moreIschemia Reperfusion Injury, Hematopoietic Stem Cells, Cell Differentiation, Humans, Ischemia, Mice, Diabetic Retinopathy, Animals, Embryonic Stem Cells, Mouse Model, Rats, Myocardial Infarction, Endothelial cell, Blood Flow, Blood Vessels, Reperfusion injury, Type 2 Diabetes Mellitus, and Mortality rate
Research Interests:
Ubiquitous protein kinase CK2 participates in a variety of key cellular functions. We have explored CK2 involvement in angiogenesis. As shown previously, CK2 inhibition reduced endothelial cell proliferation, survival and migration, tube... more
Ubiquitous protein kinase CK2 participates in a variety of key cellular functions. We have explored CK2 involvement in angiogenesis. As shown previously, CK2 inhibition reduced endothelial cell proliferation, survival and migration, tube formation, and secondary sprouting on Matrigel. Intraperitoneally administered CK2 inhibitors significantly reduced preretinal neovascularization in a mouse model of proliferative retinopathy. In this model, CK2 inhibitors had an additive effect with somatostatin analog, octreotide, resulting in marked dose reduction for the drug to achieve the same effect. CK2 inhibitors may thus emerge as potent future drugs aimed at inhibiting pathological angiogenesis. Immunostaining of the retina revealed predominant CK2 expression in astrocytes. In human diabetic retinas, mRNA levels of all CK2 subunits decreased, consistent with increased apoptosis. Importantly, a specific CK2 inhibitor prevented recruitment of bone marrow-derived hematopoietic stem cells to areas of retinal neovascularization. This may provide a novel mechanism of action of CK2 inhibitors on newly forming vessels.
Research Interests: Stem Cell, Hematopoietic Stem Cells, Molecular and cellular biology, Humans, Endothelial Cells, and 15 moreMice, Animals, Retina, Astrocyte, Cattle, Mouse Model, Endothelial cell, Combination drug therapy, Mechanism of action, Protein Kinase, Molecular and Cellular Biochemistry, Protein Kinase Inhibitors, Biochemistry and cell biology, Hematopoietic Stem Cell, and Hematopoietic Stem Cell Transplantation
Research Interests: Archives, Optical coherence tomography, Prospective studies, Humans, Diabetic Retinopathy, and 23 moreFemale, Male, Disease Severity, Vascular endothelium, Chemotaxis, Clinical Sciences, Aged, Middle Aged, Optometry and Ophthalmology, Triamcinolone Acetonide, Adult, Public health systems and services research, Clinical Ophthalmology, Type 2 Diabetes Mellitus, Growth Factor, Vascular Permeability, Vitrectomy, Enzyme Linked Immunosorbent Assay, Glucocorticoids, Control Group, Macular edema, Injections, and Vascular Endothelial Growth Factor
Research Interests: Stem Cells, Fluorescence Microscopy, Cell Adhesion, Stem Cell, Biological Sciences, and 16 moreAntibodies, Hematopoietic Stem Cells, Mice, Animals, Vascular endothelium, Bone marrow, Green Fluorescent Protein, Age related macular degeneration, Chimera, Endothelial cell, Developing nations, Vascular Endothelial Function, Choroidal Neovascularization Industry, Hematopoietic Stem Cell, Hematopoietic Stem Cell Transplantation, and Cadherins
Research Interests:
Research Interests:
Research Interests:
Research Interests: Cell Division, DNA, Humans, Diabetic Retinopathy, Female, and 11 moreMale, Polymerase Chain Reaction, Vascular endothelium, Chemotaxis, Fibroblast Growth Factor, Endothelial cell, Tissue Plasminogen Activator, Base Sequence, Recombinant Proteins, Plasminogen Activator Inhibitor, and Molecular Sequence Data
Research Interests:
The role of adenosine receptor (AdoR) antagonists in human retinal endothelial cell function in vitro has previously been determined. In this study, efficacy of AdoR antagonist administration in reducing retinal neovascularization was... more
The role of adenosine receptor (AdoR) antagonists in human retinal endothelial cell function in vitro has previously been determined. In this study, efficacy of AdoR antagonist administration in reducing retinal neovascularization was examined in a mouse pup model of oxygen-induced retinopathy. A previously described model of oxygen-induced retinal neovascularization in newborn mouse pups was used to examine the effect of various AdoR antagonists on neovascularization. The nonselective AdoR antagonist xanthine amine congener (XAC), the A(2A)-selective antagonist ZM241385, the A(2B)-selective antagonists 3-N-propylxanthine (enprofylline) and 3-isobutyl-8-pyrrolidinoxanthine (IPDX), and the A(1)-selective antagonist cyclopentyl-1,3-dipropylxanthine (CPX) were used. After the hyperoxia exposure the animals received daily intraperitoneal injections of pharmacologically relevant doses of AdoR antagonists for 5 days. Control animals received vehicle (0.1% dimethyl sulfoxide [DMSO]) alone. The animals were then killed and perfused with fluorescein-dextran. Wholemounts of retinas from one eye were prepared and examined, whereas the retinas of the contralateral eye were embedded, sectioned, and stained for counting neovascular nuclei extending beyond the internal limiting membrane into the vitreous. Angiography of wholemount retinas showed reduction of neovascular tufts in animals treated with selective A(2B) AdoR antagonists. Quantification of the extraretinal neovascular nuclei showed that only animals treated with XAC, enprofylline, or IPDX showed a significant reduction in retinal neovascularization. By contrast, neither CPX nor ZM241385 had an effect on neovascularization. The A(2B)-selective AdoR antagonists inhibited oxygen-induced retinal neovascularization in vivo and may provide a basis for developing pharmacologic therapies for the treatment of proliferative retinopathies.
Research Interests:
Research Interests:
Research Interests: Electron Microscopy, Transgenic Mice, Biological Sciences, Capillaries, Basement Membrane, and 15 moreMice, Diabetic Retinopathy, Female, Animals, Male, Vascular endothelium, Pericytes, Zinc, Metallothionein, Endothelial cell, Cross Section, Zinc Sulfate, Light microscopy, Colloidal Gold, and Plasminogen Activator Inhibitor
Plasminogen activator inhibitor-1 is secreted bidirectionally by endothelial cells, acts as the primary regulator of fibrinolysis and as a key modulator of extracellular matrix proteolysis. Elevated serum levels of plasminogen activator... more
Plasminogen activator inhibitor-1 is secreted bidirectionally by endothelial cells, acts as the primary regulator of fibrinolysis and as a key modulator of extracellular matrix proteolysis. Elevated serum levels of plasminogen activator inhibitor-1 are observed in serum of diabetic individuals. We investigated whether plasminogen activator inhibitor-1 is overexpressed in capillaries of diabetic donors with non-proliferative retinopathy compared to non-diabetic donors. We also assessed plasminogen activator inhibitor-1 expression in an animal model of retinopathy induced by exposing rabbit retinas to insulin-like growth factor-I. Colloidal gold immunocytochemistry was used to quantify plasminogen activator-1 antigen in donor retinas from diabetic subjects (n = 10) and control subjects (n = 10). This technique was also used to examine expression of plasminogen activator inhibitor-1 for correlation with retinal changes in the insulin-like growth factor-I-induced retinopathy model (n = 14). Plasminogen activator inhibitor-1 immunoreactivity was significantly increased in the retinas of all diabetic subjects as compared to controls. In the rabbit model, the expression of plasminogen activator inhibitor-1 immunoreactivity correlated with pathological retinal changes. In both the diabetic human and insulin-like growth factor-I-injected rabbit, overproduction of plasminogen activator inhibitor-1 was seen within the lumen of capillaries, within the cytoplasm of endothelial cells and in the basement membrane and extracellular matrix surrounding these capillaries. Minimal plasminogen activator inhibitor-1 was detected in the retinas of non-diabetics and in control rabbits injected with either heat-inactivated insulin-like growth factor-I or balanced salt solution. These studies support the conclusion that plasminogen activator inhibitor-1 is overexpressed in the retinal capillaries of diabetics with non-proliferative diabetic retinopathy and in rabbits with insulin-like growth factor-I-induced retinopathy.
Research Interests: Electron Microscopy, Immunohistochemistry, Extracellular Matrix, Immunocytochemistry, Humans, and 17 moreCapillaries, Basement Membrane, Diabetic Retinopathy, Female, Animals, Male, Animal Model, Aged, Middle Aged, Optometry and Ophthalmology, Adult, Endothelial cell, Rabbits, Neurosciences, Colloidal Gold, Plasminogen Activator Inhibitor, and Plasminogen Activator
Research Interests:
Proliferative retinopathies account for the majority of cases of vision loss throughout the world. Currently accepted therapy for retinopathy consists of retinal ablation by panretinal laser photocoagulation or cryotherapy. This technique... more
Proliferative retinopathies account for the majority of cases of vision loss throughout the world. Currently accepted therapy for retinopathy consists of retinal ablation by panretinal laser photocoagulation or cryotherapy. This technique is not without deleterious effects to patients, including diminished night vision, reduced peripheral vision and loss of precise vision, decreasing visual acuity by one to two lines in magnitude. One promising area of research into pharmacotherapeutics for retinopathies, especially proliferative diabetic retinopathy, involves the use of synthetic analogues of somatostatin. The rationale for somatostatin as a therapeutic agent for retinal neovascularization is discussed. Somatostatin analogues such as octreotide have shown promise as a safe and effective treatment for severe proliferative diabetic retinopathy by blocking the local and systemic production of growth hormone and insulin-like growth factor type 1 associated with angiogenesis and endothelial cell proliferation. There are also observations suggesting an autocrine and paracrine effect of somatostatin, perhaps directly on retinal cells, which are known to express somatostatin receptors (SSTR). SSTR2 and SSTR3 are the most important receptor subtypes mediating growth hormone secretion and endothelial cell cycle arrest, retinal endothelial cell apoptosis and release of insulin. Thus, analogues that target these receptor subtypes may prove more useful. Long-acting somatostatin analogues are currently being tested for treatment of diabetic retinopathy and are, in fact, the only therapeutic alternative for patients who fail panretinal photocoagulation. Whether such a therapy may also prove effective for other retinal vascular proliferative diseases such as retinopathy of prematurity and age-related macular degeneration remains an open question that deserves attention, given our new understanding of the cellular and molecular mechanisms by which somatostatin may exert its antiangiogenic effects.
Research Interests:
Research Interests: Cell Division, Antibodies, Humans, cyclic AMP, Vascular endothelium, and 13 moreFibroblast Growth Factor, Clinical Sciences, mRna expression levels, Fluorescent Antibody Technique, Time Dependent, Endothelial cell, Antisense Oligonucleotide Drugs, Protein Expression, Circulation, Cell Proliferation, Growth Factor, Culture Media, and Vascular Endothelial Growth Factor
Research Interests:
Research Interests: Stem Cells, Flow Cytometry, Confocal Microscopy, Stem Cell, Immunocytochemistry, and 15 moreTransgenic Mice, Macular Degeneration, Biological Sciences, Hematopoietic Stem Cells, Mice, Animals, Bone marrow, Age related macular degeneration, Blood Vessels, Blood Vessel, Blood cells, Adult Stem Cell, Choroidal Neovascularization Industry, Hematopoietic Stem Cell, and Hematopoietic Stem Cell Transplantation
Matrix metalloproteinases (MMPs) are a group of enzymes thought to be responsible for both normal connective tissue matrix remodelling and accelerated breakdown associated with tumour development. The current study aimed to investigate... more
Matrix metalloproteinases (MMPs) are a group of enzymes thought to be responsible for both normal connective tissue matrix remodelling and accelerated breakdown associated with tumour development. The current study aimed to investigate the immunohistochemical expression of matrix metalloproteinase 3 (MMP-3, stromelysin-1) in correlation with the expression of Basement Membrane (BM) antigen (type IV collagen, laminin), fibronectin, cathepsin D, p53, c-erbB-2, proliferative activity (Ki-67, PCNA), steroid receptor content as well as to the other conventional clinicopathological parameters in breast cancer. This study was performed on a series of frozen and paraffin sections from 84 breast cancer specimens by immunohistochemistry using the monoclonal antibody MMP-3 (Ab-1). Stromelysin-1 (ST1) was observed in about 10% of epithelial cells in the control groups (cases of fibrocystic and benign proliferative breast disease), while expression (> 10% of expression) was detected in 89.7% of tumours. The expression of ST1 in carcinoma cells was strongly associated with its presence in the stroma (p < 0.001). A significantly positive correlation was found between ST1 expression, and p53 tumour suppressor gene product (p = 0.004), and a relationship with c-erbB-2 protein and progesterone receptor status was also indicated. These findings suggest that ST1 expression in breast cancer tissue is irrespective of the expression of the extracellular matrix component, the proteolytic enzyme cathepsin D and the growth fraction of the tumour, and that it could be a potential new prognostic marker in breast cancer.
Research Interests:
Research Interests:
Research Interests: Cell Migration, Wound Healing, Adolescent, Western blotting, Cell Division, and 17 moreSignal Transduction, Biological Sciences, Humans, Basement Membrane, Diabetic Retinopathy, Female, Animals, Male, Vascular endothelium, Cattle, Aged, Middle Aged, Tenascin-C, Endothelial cell, Transforming Growth Factor Beta, Growth Factor, and Cell Survival
Research Interests: Confocal Microscopy, Stem Cell, Nature, Transgenic Mice, Hematopoietic Stem Cells, and 11 moreIschemia, Mice, Animals, Retina, Green Fluorescent Protein, Clinical Sciences, Optometry and Ophthalmology, Endothelial cell, Public health systems and services research, Hematopoietic Stem Cell, and Hematopoietic Stem Cell Transplantation
Evidence suggests the involvement of growth hormone (GH), insulin-like growth factor I (IGF-I) and somatostatin in the pathology associated with diabetic retinopathy. We examined the effect of IGF-I on human retinal endothelial cell... more
Evidence suggests the involvement of growth hormone (GH), insulin-like growth factor I (IGF-I) and somatostatin in the pathology associated with diabetic retinopathy. We examined the effect of IGF-I on human retinal endothelial cell (HREC) survival following high glucose exposure and serum starvation, examined the signalling pathways mediating the protective effect of IGF-I on HREC, and characterized somatostatin receptor-induced retinal endothelial cell death. IGF-I (10 ng/ml) protected HREC from apoptosis induced by high glucose and serum starvation. Wortmannin, a specific inhibitor of phosphotidylinositol-3-kinase, blocks the ability of IGF-I to protect HREC from apoptosis. Incubation of HREC in serum-free medium caused a time-dependent increase in c-Jun N-terminal kinase (JNK) activity, and continuous culture of HREC in the presence of IGF-I or vascular endothelial growth factor (VEGF) prevented JNK activation and arrested apoptosis. Activation of tyrosine kinase receptors results in extracellular signal-related kinase (ERK) activation and activation of ERK is required for proliferation. Both IGF-I and VEGF produced a time- and concentration-dependent increase in the activation of ERK. Type 2 and type 3 somatostatin receptors have been implicated in cell-cycle arrest and apoptosis. Activation of the type 3 receptor in HREC resulted in cell death. These studies suggest that IGF-I is critical for HREC survival, and that somatostatin analogues acting through the type 3 receptor have direct effects on retinal endothelial cells. Furthermore, it appears that the therapeutic efficacy of somatostatin analogues lies not only in systemic inhibition of GH, but also in modulating local growth factor effects.
Research Interests:
Research Interests:
Research Interests:
Research Interests:
... Capillary Cell Proliferation and Migration Maria B. Grant, Sergio Caballero, David M. Bush, and Polyxenie E. Spoerri ... Their effects on migration were assessed using modified Boyden chambers. Seven Fn-f were tested on vascular cell... more
... Capillary Cell Proliferation and Migration Maria B. Grant, Sergio Caballero, David M. Bush, and Polyxenie E. Spoerri ... Their effects on migration were assessed using modified Boyden chambers. Seven Fn-f were tested on vascular cell migration and/or prolifer-ation. ...
Research Interests:
Research Interests: Technology, Human Embryonic Stem Cells, Human embryonic stem cell, Stem Cell Transplantation, Biological Sciences, and 18 moreIschemia Reperfusion Injury, Hematopoietic Stem Cells, Cell Differentiation, Humans, Ischemia, Mice, Diabetic Retinopathy, Animals, Embryonic Stem Cells, Mouse Model, Rats, Myocardial Infarction, Endothelial cell, Blood Flow, Blood Vessels, Reperfusion injury, Type 2 Diabetes Mellitus, and Mortality rate
Research Interests:
Ubiquitous protein kinase CK2 participates in a variety of key cellular functions. We have explored CK2 involvement in angiogenesis. As shown previously, CK2 inhibition reduced endothelial cell proliferation, survival and migration, tube... more
Ubiquitous protein kinase CK2 participates in a variety of key cellular functions. We have explored CK2 involvement in angiogenesis. As shown previously, CK2 inhibition reduced endothelial cell proliferation, survival and migration, tube formation, and secondary sprouting on Matrigel. Intraperitoneally administered CK2 inhibitors significantly reduced preretinal neovascularization in a mouse model of proliferative retinopathy. In this model, CK2 inhibitors had an additive effect with somatostatin analog, octreotide, resulting in marked dose reduction for the drug to achieve the same effect. CK2 inhibitors may thus emerge as potent future drugs aimed at inhibiting pathological angiogenesis. Immunostaining of the retina revealed predominant CK2 expression in astrocytes. In human diabetic retinas, mRNA levels of all CK2 subunits decreased, consistent with increased apoptosis. Importantly, a specific CK2 inhibitor prevented recruitment of bone marrow-derived hematopoietic stem cells to areas of retinal neovascularization. This may provide a novel mechanism of action of CK2 inhibitors on newly forming vessels.
Research Interests: Stem Cell, Hematopoietic Stem Cells, Molecular and cellular biology, Humans, Endothelial Cells, and 15 moreMice, Animals, Retina, Astrocyte, Cattle, Mouse Model, Endothelial cell, Combination drug therapy, Mechanism of action, Protein Kinase, Molecular and Cellular Biochemistry, Protein Kinase Inhibitors, Biochemistry and cell biology, Hematopoietic Stem Cell, and Hematopoietic Stem Cell Transplantation
Research Interests: Archives, Optical coherence tomography, Prospective studies, Humans, Diabetic Retinopathy, and 23 moreFemale, Male, Disease Severity, Vascular endothelium, Chemotaxis, Clinical Sciences, Aged, Middle Aged, Optometry and Ophthalmology, Triamcinolone Acetonide, Adult, Public health systems and services research, Clinical Ophthalmology, Type 2 Diabetes Mellitus, Growth Factor, Vascular Permeability, Vitrectomy, Enzyme Linked Immunosorbent Assay, Glucocorticoids, Control Group, Macular edema, Injections, and Vascular Endothelial Growth Factor
Research Interests: Stem Cells, Fluorescence Microscopy, Cell Adhesion, Stem Cell, Biological Sciences, and 16 moreAntibodies, Hematopoietic Stem Cells, Mice, Animals, Vascular endothelium, Bone marrow, Green Fluorescent Protein, Age related macular degeneration, Chimera, Endothelial cell, Developing nations, Vascular Endothelial Function, Choroidal Neovascularization Industry, Hematopoietic Stem Cell, Hematopoietic Stem Cell Transplantation, and Cadherins
Research Interests:
Research Interests:
Research Interests:
Research Interests: Cell Division, DNA, Humans, Diabetic Retinopathy, Female, and 11 moreMale, Polymerase Chain Reaction, Vascular endothelium, Chemotaxis, Fibroblast Growth Factor, Endothelial cell, Tissue Plasminogen Activator, Base Sequence, Recombinant Proteins, Plasminogen Activator Inhibitor, and Molecular Sequence Data
Research Interests:
The role of adenosine receptor (AdoR) antagonists in human retinal endothelial cell function in vitro has previously been determined. In this study, efficacy of AdoR antagonist administration in reducing retinal neovascularization was... more
The role of adenosine receptor (AdoR) antagonists in human retinal endothelial cell function in vitro has previously been determined. In this study, efficacy of AdoR antagonist administration in reducing retinal neovascularization was examined in a mouse pup model of oxygen-induced retinopathy. A previously described model of oxygen-induced retinal neovascularization in newborn mouse pups was used to examine the effect of various AdoR antagonists on neovascularization. The nonselective AdoR antagonist xanthine amine congener (XAC), the A(2A)-selective antagonist ZM241385, the A(2B)-selective antagonists 3-N-propylxanthine (enprofylline) and 3-isobutyl-8-pyrrolidinoxanthine (IPDX), and the A(1)-selective antagonist cyclopentyl-1,3-dipropylxanthine (CPX) were used. After the hyperoxia exposure the animals received daily intraperitoneal injections of pharmacologically relevant doses of AdoR antagonists for 5 days. Control animals received vehicle (0.1% dimethyl sulfoxide [DMSO]) alone. The animals were then killed and perfused with fluorescein-dextran. Wholemounts of retinas from one eye were prepared and examined, whereas the retinas of the contralateral eye were embedded, sectioned, and stained for counting neovascular nuclei extending beyond the internal limiting membrane into the vitreous. Angiography of wholemount retinas showed reduction of neovascular tufts in animals treated with selective A(2B) AdoR antagonists. Quantification of the extraretinal neovascular nuclei showed that only animals treated with XAC, enprofylline, or IPDX showed a significant reduction in retinal neovascularization. By contrast, neither CPX nor ZM241385 had an effect on neovascularization. The A(2B)-selective AdoR antagonists inhibited oxygen-induced retinal neovascularization in vivo and may provide a basis for developing pharmacologic therapies for the treatment of proliferative retinopathies.
Research Interests:
Research Interests:
Research Interests: Electron Microscopy, Transgenic Mice, Biological Sciences, Capillaries, Basement Membrane, and 15 moreMice, Diabetic Retinopathy, Female, Animals, Male, Vascular endothelium, Pericytes, Zinc, Metallothionein, Endothelial cell, Cross Section, Zinc Sulfate, Light microscopy, Colloidal Gold, and Plasminogen Activator Inhibitor
Plasminogen activator inhibitor-1 is secreted bidirectionally by endothelial cells, acts as the primary regulator of fibrinolysis and as a key modulator of extracellular matrix proteolysis. Elevated serum levels of plasminogen activator... more
Plasminogen activator inhibitor-1 is secreted bidirectionally by endothelial cells, acts as the primary regulator of fibrinolysis and as a key modulator of extracellular matrix proteolysis. Elevated serum levels of plasminogen activator inhibitor-1 are observed in serum of diabetic individuals. We investigated whether plasminogen activator inhibitor-1 is overexpressed in capillaries of diabetic donors with non-proliferative retinopathy compared to non-diabetic donors. We also assessed plasminogen activator inhibitor-1 expression in an animal model of retinopathy induced by exposing rabbit retinas to insulin-like growth factor-I. Colloidal gold immunocytochemistry was used to quantify plasminogen activator-1 antigen in donor retinas from diabetic subjects (n = 10) and control subjects (n = 10). This technique was also used to examine expression of plasminogen activator inhibitor-1 for correlation with retinal changes in the insulin-like growth factor-I-induced retinopathy model (n = 14). Plasminogen activator inhibitor-1 immunoreactivity was significantly increased in the retinas of all diabetic subjects as compared to controls. In the rabbit model, the expression of plasminogen activator inhibitor-1 immunoreactivity correlated with pathological retinal changes. In both the diabetic human and insulin-like growth factor-I-injected rabbit, overproduction of plasminogen activator inhibitor-1 was seen within the lumen of capillaries, within the cytoplasm of endothelial cells and in the basement membrane and extracellular matrix surrounding these capillaries. Minimal plasminogen activator inhibitor-1 was detected in the retinas of non-diabetics and in control rabbits injected with either heat-inactivated insulin-like growth factor-I or balanced salt solution. These studies support the conclusion that plasminogen activator inhibitor-1 is overexpressed in the retinal capillaries of diabetics with non-proliferative diabetic retinopathy and in rabbits with insulin-like growth factor-I-induced retinopathy.
Research Interests: Electron Microscopy, Immunohistochemistry, Extracellular Matrix, Immunocytochemistry, Humans, and 17 moreCapillaries, Basement Membrane, Diabetic Retinopathy, Female, Animals, Male, Animal Model, Aged, Middle Aged, Optometry and Ophthalmology, Adult, Endothelial cell, Rabbits, Neurosciences, Colloidal Gold, Plasminogen Activator Inhibitor, and Plasminogen Activator
Research Interests:
Proliferative retinopathies account for the majority of cases of vision loss throughout the world. Currently accepted therapy for retinopathy consists of retinal ablation by panretinal laser photocoagulation or cryotherapy. This technique... more
Proliferative retinopathies account for the majority of cases of vision loss throughout the world. Currently accepted therapy for retinopathy consists of retinal ablation by panretinal laser photocoagulation or cryotherapy. This technique is not without deleterious effects to patients, including diminished night vision, reduced peripheral vision and loss of precise vision, decreasing visual acuity by one to two lines in magnitude. One promising area of research into pharmacotherapeutics for retinopathies, especially proliferative diabetic retinopathy, involves the use of synthetic analogues of somatostatin. The rationale for somatostatin as a therapeutic agent for retinal neovascularization is discussed. Somatostatin analogues such as octreotide have shown promise as a safe and effective treatment for severe proliferative diabetic retinopathy by blocking the local and systemic production of growth hormone and insulin-like growth factor type 1 associated with angiogenesis and endothelial cell proliferation. There are also observations suggesting an autocrine and paracrine effect of somatostatin, perhaps directly on retinal cells, which are known to express somatostatin receptors (SSTR). SSTR2 and SSTR3 are the most important receptor subtypes mediating growth hormone secretion and endothelial cell cycle arrest, retinal endothelial cell apoptosis and release of insulin. Thus, analogues that target these receptor subtypes may prove more useful. Long-acting somatostatin analogues are currently being tested for treatment of diabetic retinopathy and are, in fact, the only therapeutic alternative for patients who fail panretinal photocoagulation. Whether such a therapy may also prove effective for other retinal vascular proliferative diseases such as retinopathy of prematurity and age-related macular degeneration remains an open question that deserves attention, given our new understanding of the cellular and molecular mechanisms by which somatostatin may exert its antiangiogenic effects.
Research Interests:
Research Interests: Cell Division, Antibodies, Humans, cyclic AMP, Vascular endothelium, and 13 moreFibroblast Growth Factor, Clinical Sciences, mRna expression levels, Fluorescent Antibody Technique, Time Dependent, Endothelial cell, Antisense Oligonucleotide Drugs, Protein Expression, Circulation, Cell Proliferation, Growth Factor, Culture Media, and Vascular Endothelial Growth Factor
Research Interests:
Matrix metalloproteinases (MMPs) are a group of enzymes thought to be responsible for both normal connective tissue matrix remodelling and accelerated breakdown associated with tumour development. The current study aimed to investigate... more
Matrix metalloproteinases (MMPs) are a group of enzymes thought to be responsible for both normal connective tissue matrix remodelling and accelerated breakdown associated with tumour development. The current study aimed to investigate the immunohistochemical expression of matrix metalloproteinase 3 (MMP-3, stromelysin-1) in correlation with the expression of Basement Membrane (BM) antigen (type IV collagen, laminin), fibronectin, cathepsin D, p53, c-erbB-2, proliferative activity (Ki-67, PCNA), steroid receptor content as well as to the other conventional clinicopathological parameters in breast cancer. This study was performed on a series of frozen and paraffin sections from 84 breast cancer specimens by immunohistochemistry using the monoclonal antibody MMP-3 (Ab-1). Stromelysin-1 (ST1) was observed in about 10% of epithelial cells in the control groups (cases of fibrocystic and benign proliferative breast disease), while expression (> 10% of expression) was detected in 89.7% of tumours. The expression of ST1 in carcinoma cells was strongly associated with its presence in the stroma (p < 0.001). A significantly positive correlation was found between ST1 expression, and p53 tumour suppressor gene product (p = 0.004), and a relationship with c-erbB-2 protein and progesterone receptor status was also indicated. These findings suggest that ST1 expression in breast cancer tissue is irrespective of the expression of the extracellular matrix component, the proteolytic enzyme cathepsin D and the growth fraction of the tumour, and that it could be a potential new prognostic marker in breast cancer.
Research Interests:
Research Interests: Cell Migration, Wound Healing, Adolescent, Western blotting, Cell Division, and 17 moreSignal Transduction, Biological Sciences, Humans, Basement Membrane, Diabetic Retinopathy, Female, Animals, Male, Vascular endothelium, Cattle, Aged, Middle Aged, Tenascin-C, Endothelial cell, Transforming Growth Factor Beta, Growth Factor, and Cell Survival
Evidence suggests the involvement of growth hormone (GH), insulin-like growth factor I (IGF-I) and somatostatin in the pathology associated with diabetic retinopathy. We examined the effect of IGF-I on human retinal endothelial cell... more
Evidence suggests the involvement of growth hormone (GH), insulin-like growth factor I (IGF-I) and somatostatin in the pathology associated with diabetic retinopathy. We examined the effect of IGF-I on human retinal endothelial cell (HREC) survival following high glucose exposure and serum starvation, examined the signalling pathways mediating the protective effect of IGF-I on HREC, and characterized somatostatin receptor-induced retinal endothelial cell death. IGF-I (10 ng/ml) protected HREC from apoptosis induced by high glucose and serum starvation. Wortmannin, a specific inhibitor of phosphotidylinositol-3-kinase, blocks the ability of IGF-I to protect HREC from apoptosis. Incubation of HREC in serum-free medium caused a time-dependent increase in c-Jun N-terminal kinase (JNK) activity, and continuous culture of HREC in the presence of IGF-I or vascular endothelial growth factor (VEGF) prevented JNK activation and arrested apoptosis. Activation of tyrosine kinase receptors results in extracellular signal-related kinase (ERK) activation and activation of ERK is required for proliferation. Both IGF-I and VEGF produced a time- and concentration-dependent increase in the activation of ERK. Type 2 and type 3 somatostatin receptors have been implicated in cell-cycle arrest and apoptosis. Activation of the type 3 receptor in HREC resulted in cell death. These studies suggest that IGF-I is critical for HREC survival, and that somatostatin analogues acting through the type 3 receptor have direct effects on retinal endothelial cells. Furthermore, it appears that the therapeutic efficacy of somatostatin analogues lies not only in systemic inhibition of GH, but also in modulating local growth factor effects.