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Amorim S, Gaspar AP, Degens H, Cendoroglo MS, de Mello Franco FG, Ritti-Dias RM, Cucato GG, Rolnick N, de Matos LDNJ. The Effect of a Single Bout of Resistance Exercise with Blood Flow Restriction on Arterial Stiffness in Older People with Slow Gait Speed: A Pilot Randomized Study. J Cardiovasc Dev Dis 2022; 9:jcdd9030085. [PMID: 35323633 PMCID: PMC8950238 DOI: 10.3390/jcdd9030085] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/13/2022] [Accepted: 01/17/2022] [Indexed: 11/20/2022] Open
Abstract
Purpose: Low-intensity resistance exercise with moderate blood-flow restriction (LIRE-BFR) is a new trending form of exercises worldwide. The purpose of this study was to compare the acute effect of a single bout of traditional resistance exercise (TRE) and LIRE-BFR on arterial stiffness in older people with slow gait speeds. Methods: This was a randomized, controlled clinical study. Seventeen older adults (3 men; 14 women; 82 ± 5 years old) completed a session of TRE (n = 7) or LIRE-BFR (n = 10). At baseline and after 60 min post-exercise, participants were subject to blood pressure measurement, heart rate measurements and a determination of arterial stiffness parameters. Results: There was no significant difference between the TRE and LIRE-BFR group at baseline. Pulse-wave velocity increased in both groups (p < 0.05) post-exercise with no between-group differences. Both exercise modalities did not produce any adverse events. The increase in systolic blood pressure, pulse pressure, augmentation pressure and pulse wave velocity (all p > 0.05) were similar after both TRE and LIRE-BFR. Conclusion: TRE and LIRE-BFR had similar responses regarding hemodynamic parameters and pulse-wave velocity in older people with slow gait speed. Long-term studies should assess the cardiovascular risk and safety of LIRE-BFR training in this population.
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Affiliation(s)
- Samuel Amorim
- Hospital Israelita Albert Einstein, Sao Paulo 05652-900, Brazil; (S.A.); (A.P.G.); (F.G.d.M.F.)
| | - Alexandra Passos Gaspar
- Hospital Israelita Albert Einstein, Sao Paulo 05652-900, Brazil; (S.A.); (A.P.G.); (F.G.d.M.F.)
| | - Hans Degens
- Research Centre for Musculoskeletal Science & Sports Medicine, Manchester Metropolitan University, Manchester M1 5GD, UK;
| | - Maysa Seabra Cendoroglo
- Division of Geriatrics, Paulista Medical School, The Federal University, Sao Paulo 04020-050, Brazil;
| | | | - Raphael Mendes Ritti-Dias
- Postgraduate Program in Rehabilitation Science, Universidade Nove de Julho, Sao Paulo 01525-000, Brazil;
| | | | - Nicholas Rolnick
- Department of Health Sciences, Lehman College, City University of New York (CUNY), New York, NY 10468, USA;
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Oxidative Stress, Vascular Endothelium, and the Pathology of Neurodegeneration in Retina. Antioxidants (Basel) 2022; 11:antiox11030543. [PMID: 35326193 PMCID: PMC8944517 DOI: 10.3390/antiox11030543] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 03/07/2022] [Accepted: 03/10/2022] [Indexed: 02/06/2023] Open
Abstract
Oxidative stress (OS) is an imbalance between free radicals/ROS and antioxidants, which evokes a biological response and is an important risk factor for diseases, in both the cardiovascular system and central nervous system (CNS). The underlying mechanisms driving pathophysiological complications that arise from OS remain largely unclear. The vascular endothelium is emerging as a primary target of excessive glucocorticoid and catecholamine action. Endothelial dysfunction (ED) has been implicated to play a crucial role in the development of neurodegeneration in the CNS. The retina is known as an extension of the CNS. Stress and endothelium dysfunction are suspected to be interlinked and associated with neurodegenerative diseases in the retina as well. In this narrative review, we explore the role of OS-led ED in the retina by focusing on mechanistic links between OS and ED, ED in the pathophysiology of different retinal neurodegenerative conditions, and how a better understanding of the role of endothelial function could lead to new therapeutic approaches for neurodegenerative diseases in the retina.
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3
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Gene Therapy of Chronic Limb-Threatening Ischemia: Vascular Medical Perspectives. J Clin Med 2022; 11:jcm11051282. [PMID: 35268373 PMCID: PMC8910863 DOI: 10.3390/jcm11051282] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 02/21/2022] [Accepted: 02/21/2022] [Indexed: 12/27/2022] Open
Abstract
A decade ago, gene therapy seemed to be a promising approach for the treatment of chronic limb-threatening ischemia, providing new perspectives for patients without conventional, open or endovascular therapeutic options by potentially enabling neo-angiogenesis. Yet, until now, the results have been far from a safe and routine clinical application. In general, there are two approaches for inserting exogenous genes in a host genome: transduction and transfection. In case of transduction, viral vectors are used to introduce genes into cells, and depending on the selected strain of the virus, a transient or stable duration of protein production can be achieved. In contrast, the transfection of DNA is transmitted by chemical or physical processes such as lipofection, electro- or sonoporation. Relevant risks of gene therapy may be an increasing neo-vascularization in undesired tissue. The risks of malignant transformation and inflammation are the potential drawbacks. Additionally, atherosclerotic plaques can be destabilized by the increased angiogenesis, leading to arterial thrombosis. Clinical trials from pilot studies to Phase II and III studies on angiogenic gene therapy show mainly a mixed picture of positive and negative final results; thus, the role of gene therapy in vascular occlusive disease remains unclear.
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Stepanov YV, Golovynska I, Golovynskyi S, Garmanchuk LV, Gorbach O, Stepanova LI, Khranovska N, Ostapchenko LI, Ohulchanskyy TY, Qu J. Red and near infrared light-stimulated angiogenesis mediated via Ca 2+ influx, VEGF production and NO synthesis in endothelial cells in macrophage or malignant environments. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY. B, BIOLOGY 2022; 227:112388. [PMID: 35074677 DOI: 10.1016/j.jphotobiol.2022.112388] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 01/02/2022] [Accepted: 01/08/2022] [Indexed: 12/19/2022]
Abstract
Irradiation with red or near-infrared (NIR) light in low level light therapy (LLLT) is found to stimulate cellular processes and bioenergetics, resulting in enhanced wound healing, pain control, neurodegenerative diseases treatment, etc. During light irradiation of tissues and organs, different cells are affected, though the connection between photostimulation of cells and their environmental conditions remains poorly understood. In this report, red/NIR light-stimulated angiogenesis is investigated using endothelial cells in vitro, with a focus on the capillary-like structure (CLS) formation and the respective biochemical processes in cells under conditions proximate to a healthy or malignant environment, which strongly defines angiogenesis. To model environmental conditions for endotheliocytes in vitro, the cell culture environment was supplemented by an augmented conditioned medium from macrophages or cancer cells. The biochemical processes in endothelial cell cultures were investigated with and without irradiation by red (650 nm) and near-infrared (808 nm) laser diodes and under normoxia or hypoxia conditions. A light-stimulated angiogenesis has been found, with a more efficient stimulation by 650 nm light compared to 808 nm light. It was shown that the irradiation with light promoted extracellular Ca2+ influx, fostered cell cycle progression, proliferation and NO generation in endothelial cells, and caused an increase in vascular endothelial growth factor (VEGF) production by endothelial cells and M2 macrophages under hypoxia conditions. The activation of VEGF production by macrophages was found to be associated with an increase in the number of M2 macrophages after light irradiation under hypoxia conditions. Thus, a new pathway of an activation of the endothelial cell metabolism, which is related with the extracellular Ca2+ influx after light irradiation, has been revealed. STATEMENT OF SIGNIFICANCE: Red/NIR light-stimulated angiogenesis has been studied using endothelial cells in vitro, with focus on CLS formation and the respective biochemical processes in cell models proximate to a healthy or malignant environment. A light-stimulated angiogenesis has been found, stimulated via extracellular Ca2+ influx, cell cycle progression, proliferation and NO generation, VEGF production increase by endothelial cells under hypoxia conditions.
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Affiliation(s)
- Yurii V Stepanov
- Center for Biomedical Optics and Photonics, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, PR China
| | - Iuliia Golovynska
- Center for Biomedical Optics and Photonics, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, PR China
| | - Sergii Golovynskyi
- Center for Biomedical Optics and Photonics, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, PR China
| | - Liudmyla V Garmanchuk
- Institute of Biology and Medicine, Taras Shevchenko National University of Kyiv, Kyiv 01601, Ukraine
| | - Oleksandr Gorbach
- Laboratory of Experimental Oncology, National Cancer Institute of Ukraine, Kyiv 03022, Ukraine
| | - Liudmyla I Stepanova
- Institute of Biology and Medicine, Taras Shevchenko National University of Kyiv, Kyiv 01601, Ukraine
| | - Natalia Khranovska
- Laboratory of Experimental Oncology, National Cancer Institute of Ukraine, Kyiv 03022, Ukraine
| | - Liudmyla I Ostapchenko
- Institute of Biology and Medicine, Taras Shevchenko National University of Kyiv, Kyiv 01601, Ukraine
| | - Tymish Y Ohulchanskyy
- Center for Biomedical Optics and Photonics, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, PR China.
| | - Junle Qu
- Center for Biomedical Optics and Photonics, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, PR China.
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Aşikgarip N, Yenerel NM. Comparison of the effects of intravitreal ranibizumab and aflibercept on retinal vessel diameters in patients with diabetic macular edema. Photodiagnosis Photodyn Ther 2021; 34:102282. [PMID: 33813015 DOI: 10.1016/j.pdpdt.2021.102282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/26/2021] [Accepted: 03/29/2021] [Indexed: 10/21/2022]
Abstract
PURPOSE To evaluate and compare the effects of intravitreal ranibizumab and aflibercept treatment on retinal vessel diameters in patients with diabetic macular edema (DME). METHODS Thirty initial-treatment naïve patients with DME who received three loading doses at monthly intervals of intravitreal ranibizumab or aflibercept were retrospectively reviewed. The diameters of the central retinal artery and vein sections at a distance of 1500 microns from the optical disc boundary were measured and evaluated at baseline and after the first, second, and third month of the treatment, using infrared images from optical coherence tomography (OCT) (Heidelberg Engineering, Heidelberg, Germany). RESULTS In the superotemporal artery (STA) measurements, the mean basal vessel diameter decreased from 110.00 ± 17.25 μm to 102.60 ± 16.90 μm (p = 0.001) in the third month of the treatment in the ranibizumab group. In the aflibercept group, measurements of the basal STA vessel diameter decreased from 110.20 ± 21.25 μm to 103.93 ± 19.03 μm (p = 0.001) at the third month. The mean basal inferotemporal artery (ITA) vessel diameter was significantly decreased at the third month in both ranibizumab (p = 0.001) and aflibercept groups (p = 0.005). In the superotemporal vein (STV) and inferotemporal vein (ITV) measurements, vessel diameters were found significantly decreased at the end of the third month compared with basal measurements in both the ranibizumab (p = 0.001; p = 0.001, respectively) and aflibercept (p = 0.001; p = 0.004, respectively) treatment groups. The retinal vessel measurements were not found to differ significantly between the two intravitreal treatment agents (p > 0.05). CONCLUSION Both intravitreal ranibizumab and aflibercept agents cause a significant narrowing in the retinal vessel diameters in patients with DME after three loading doses at monthly intervals.
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Affiliation(s)
- Nazife Aşikgarip
- Kırşehir Ahi Evran Training and Research Hospital, Department of Opthalmology, Kırşehir, Turkey.
| | - Nursal Melda Yenerel
- University of Health Sciences, Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey
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Li J, He J, Zhang X, Li J, Zhao P, Fei P. TSP1 ameliorates age-related macular degeneration by regulating the STAT3-iNOS signaling pathway. Exp Cell Res 2020; 388:111811. [PMID: 31899207 DOI: 10.1016/j.yexcr.2019.111811] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 12/25/2019] [Accepted: 12/28/2019] [Indexed: 12/11/2022]
Abstract
Age-related macular degeneration is a progressive ocular disease that is the leading cause of vision loss among elderly. AMD usually is divided into two types: wet and dry AMD, which is linked with inflammation. Choroidal Neovascularization (CNV) formation or wet AMD is also associated with oxidative stress. Previously, TSP1 has been shown to have a significant alleviating effect on CNV in TSP1 knockout (TSP1-/-) mice. However, the mechanism by which TSP1 ameliorates CNV remains unclear. Here we report that TSP1 reduces nitric oxide production to prevent cells from forming tubes formation and reduced the levels of vascular endothelial growth factor (VEGF) and lipid peroxides (LPO) during oxidative stress. We measured RF/6A cell viability by CCK-8 assay and apoptosis by flow cytometry. RF/6A cell were transfected with TSP1 and STAT3 overexpression, and then the mRNA and protein levels of TSP1 and also the signal pathways were detected by qRT-PCR and Western blot analysis. Migration assays were performed using a transwell system. Co-Immunoprecipitation was used to analyze the binding relationship between CD47 and SHP-2. The results show that overexpression of TSP1 alleviated the damage of oxidative stress to RF/6A cells including increased cell activity and migration, decreased apoptosis and reduced migration compared to the control group. SHP-2 was activated by TSP1 through its receptor CD47 and STAT3 phosphorylation was reduced by activation of SHP-2, thereby blocking STAT3-iNOS pathway and reducing NO concentration in RF/6A cells ultimately protecting them from oxidative stress. Finally, the CNV mice model confirmed that TSP1 overexpression could protect the mice against CNV in vivo, modified the antioxidants levels and decreased the expression of TNF-α and IL-6 under laser irradiation. These results indicate a potential mechanism of TSP1 to slow down formation of CNV in wet AMD, which may bring hope for new treatment strategies.
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Affiliation(s)
- Jing Li
- Department of Ophthalmology, Xinhua Hospital, Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China
| | - Jiaqi He
- Department of General Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai, 201104, China
| | - Xiang Zhang
- Department of Ophthalmology, Xinhua Hospital, Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China
| | - Jiakai Li
- Department of Ophthalmology, Xinhua Hospital, Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China
| | - Peiquan Zhao
- Department of Ophthalmology, Xinhua Hospital, Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China.
| | - Ping Fei
- Department of Ophthalmology, Xinhua Hospital, Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China.
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Giacalone JC, Miller MJ, Workalemahu G, Reutzel AJ, Ochoa D, Whitmore SS, Stone EM, Tucker BA, Mullins RF. Generation of an immortalized human choroid endothelial cell line (iChEC-1) using an endothelial cell specific promoter. Microvasc Res 2018; 123:50-57. [PMID: 30571950 DOI: 10.1016/j.mvr.2018.12.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Revised: 12/03/2018] [Accepted: 12/16/2018] [Indexed: 01/04/2023]
Abstract
Age-related macular degeneration (AMD) is a common cause of blindness worldwide. While recent studies have revealed that the loss of choroidal endothelial cells (ChECs) is critical to the disease pathogenesis of dry AMD, in vitro studies are needed to fully elucidate the disease mechanism. However, these studies remain hindered due to the lack of publically available human ChEC lines. To address this need, ChECs were harvested form donor tissue and enriched for by using magnetic cell separation using anti-CD31 conjugated microbeads. Next, lenti-viral vectors with endothelial-specific promoters driving genes necessary for immortalization, CDH5p-hTERT and CDH5p TAg, were generated. Stable integration of both gene cassettes allowed cells to maintain their proliferative state and yielded an immortalized cell line (iChEC-1). Immunocytochemical analysis of iChEC-1 confirmed the expression of important ChEC markers such as CA4, a marker of choriocapillaris endothelial cells, CDH5, and CD34, pan-endothelial cell markers. qRT-PCR analysis of expanded clones from iChEC-1 further showed that the line maintained expression of other important endothelial markers, vWF, PECAM1, and PLVAP, similar to primary cells. Functional responses were characterized by tube-forming assays and repopulation of decellularized choroid with the immortalized cell line. In conclusion, the iChEC-1 line presents a suitable immortalized human ChEC line for future in vitro studies of AMD.
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Affiliation(s)
- Joseph C Giacalone
- Institute for Vision Research, The University of Iowa, Iowa City, IA, USA; Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, IA, USA
| | - Matthew J Miller
- Institute for Vision Research, The University of Iowa, Iowa City, IA, USA; Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, IA, USA
| | - Grefachew Workalemahu
- Institute for Vision Research, The University of Iowa, Iowa City, IA, USA; Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, IA, USA
| | - Austin J Reutzel
- Institute for Vision Research, The University of Iowa, Iowa City, IA, USA; Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, IA, USA
| | - Dalyz Ochoa
- Institute for Vision Research, The University of Iowa, Iowa City, IA, USA; Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, IA, USA
| | - S Scott Whitmore
- Institute for Vision Research, The University of Iowa, Iowa City, IA, USA; Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, IA, USA
| | - Edwin M Stone
- Institute for Vision Research, The University of Iowa, Iowa City, IA, USA; Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, IA, USA
| | - Budd A Tucker
- Institute for Vision Research, The University of Iowa, Iowa City, IA, USA; Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, IA, USA
| | - Robert F Mullins
- Institute for Vision Research, The University of Iowa, Iowa City, IA, USA; Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, IA, USA.
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Barbee KA, Parikh JB, Liu Y, Buerk DG, Jaron D. Effect of spatial heterogeneity and colocalization of eNOS and capacitative calcium entry channels on shear stress-induced NO production by endothelial cells: A modeling approach. Cell Mol Bioeng 2018; 11:143-155. [PMID: 30288177 DOI: 10.1007/s12195-018-0520-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Introduction Colocalization of endothelial nitric oxide synthase (eNOS) and capacitative Ca2+ entry (CCE) channels in microdomains such as cavaeolae in endothelial cells (ECs) has been shown to significantly affect intracellular Ca2+ dynamics and NO production, but the effect has not been well quantified. Methods We developed a two-dimensional continuum model of an EC integrating shear stress-mediated ATP production, intracellular Ca2+ mobilization, and eNOS activation to investigate the effects of spatial colocalization of plasma membrane eNOS and CCE channels on Ca2+ dynamics and NO production in response to flow-induced shear stress. Our model examines the hypothesis that subcellular colocalization of cellular components can be critical for optimal coupling of NO production to blood flow. Results Our simulations predict that heterogeneity of CCE can result in formation of microdomains with significantly higher Ca2+ compared to the average cytosolic Ca2+. Ca2+ buffers with lower or no mobility further enhanced Ca2+ gradients relative to mobile buffers. Colocalization of eNOS to CCE channels significantly increased NO production. Conclusions Our results provide quantitative understanding for the role of spatial heterogeneity and the compartmentalization of signals in regulation of shear stress-induced NO production.
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Affiliation(s)
- Kenneth A Barbee
- School of Biomedical Engineering, Science and Health Systems, Drexel University, 3140 Market St., Bossone 704, Philadelphia, PA 19104 USA
| | - Jaimit B Parikh
- IBM Thomas J. Watson Research Center, 1101 Kitchawan Rd., Yorktown Heights, NY USA 10598
| | - Yien Liu
- School of Biomedical Engineering, Science and Health Systems, Drexel University, 3140 Market St., Bossone 704, Philadelphia, PA 19104 USA
| | - Donald G Buerk
- School of Biomedical Engineering, Science and Health Systems, Drexel University, 3140 Market St., Bossone 704, Philadelphia, PA 19104 USA
| | - Dov Jaron
- School of Biomedical Engineering, Science and Health Systems, Drexel University, 3140 Market St., Bossone 704, Philadelphia, PA 19104 USA
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Rao S, Santhakumar AB, Chinkwo KA, Vanniasinkam T, Luo J, Blanchard CL. Chemopreventive Potential of Cereal Polyphenols. Nutr Cancer 2018; 70:913-927. [PMID: 30273076 DOI: 10.1080/01635581.2018.1491609] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
It has been identified that diet is one of the major contributing factors associated with the development of cancer and other chronic pathologies. In the recent years, supplementing regular diet with food and/or its components that contain chemopreventive properties has been considered an effective approach in reducing the incidence of cancer and other lifestyle associated diseases. This systematic review provides an exhaustive summary of the chemopreventive properties exhibited by everyday dietary ingredients such as rice, barley, oats, and sorghum. The studies both in vitro and in vivo reviewed have highlighted the potential role of their polyphenolic content as chemopreventive agents. Polyphenolic compounds including anthocyanins, tricin, protocatechualdehyde, avenanthramide, and 3-deoxyanthocyanins found in rice, barley, oats, and sorghum, respectively, were identified as compounds with potent bioactivity. Studies demonstrated that cereal polyphenols are likely to have chemopreventive activities, particularly those found in pigmented varieties. In conclusion, findings suggest that the consumption of pigmented cereals could potentially have an important role as a natural complementary cancer preventive therapeutic. However, further studies to develop a complete understanding of the mechanisms by which phenolic compounds inhibit cancerous cell proliferation are warranted.
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Affiliation(s)
- Shiwangni Rao
- a School of Biomedical Sciences , Charles Sturt University , Wagga Wagga , New South Wales , Australia.,b Australian Research Council (ARC) Industrial Transformation Training Centre (ITTC) for Functional Grains, Graham Centre for Agricultural Innovation, Charles Sturt University , Wagga Wagga , New South Wales , Australia
| | - Abishek B Santhakumar
- a School of Biomedical Sciences , Charles Sturt University , Wagga Wagga , New South Wales , Australia.,b Australian Research Council (ARC) Industrial Transformation Training Centre (ITTC) for Functional Grains, Graham Centre for Agricultural Innovation, Charles Sturt University , Wagga Wagga , New South Wales , Australia
| | - Kenneth A Chinkwo
- a School of Biomedical Sciences , Charles Sturt University , Wagga Wagga , New South Wales , Australia.,b Australian Research Council (ARC) Industrial Transformation Training Centre (ITTC) for Functional Grains, Graham Centre for Agricultural Innovation, Charles Sturt University , Wagga Wagga , New South Wales , Australia
| | - Thiru Vanniasinkam
- a School of Biomedical Sciences , Charles Sturt University , Wagga Wagga , New South Wales , Australia
| | - Jixun Luo
- c New South Wales Department of Primary Industries , Yanco Agricultural Institute , Yanco , New South Wales , Australia
| | - Christopher L Blanchard
- a School of Biomedical Sciences , Charles Sturt University , Wagga Wagga , New South Wales , Australia.,b Australian Research Council (ARC) Industrial Transformation Training Centre (ITTC) for Functional Grains, Graham Centre for Agricultural Innovation, Charles Sturt University , Wagga Wagga , New South Wales , Australia
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Das UN. Angiogenic, Antiangiogenic Molecules, and Bioactive Lipids in Preeclampsia. Am J Hypertens 2017; 30:864-870. [PMID: 28830084 DOI: 10.1093/ajh/hpx120] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Accepted: 06/30/2017] [Indexed: 12/24/2022] Open
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Corvi F, La Spina C, Benatti L, Querques L, Lattanzio R, Bandello F, Querques G. Impact of Intravitreal Ranibizumab on Vessel Functionality in Patients With Retinal Vein Occlusion. Am J Ophthalmol 2015; 160:45-52.e1. [PMID: 25896458 DOI: 10.1016/j.ajo.2015.04.019] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2014] [Revised: 04/12/2015] [Accepted: 04/14/2015] [Indexed: 11/30/2022]
Abstract
PURPOSE To investigate the short-term effects of intravitreal ranibizumab on retinal vessel functionality in patients with retinal vein occlusion (RVO). DESIGN Prospective, interventional case series. METHODS We enrolled 11 eyes of 11 consecutive treatment-naïve patients with macular edema secondary to RVO. All patients underwent a complete ophthalmic evaluation, including optical coherence tomography and dynamic and static retinal vessel analysis, using the Dynamic Vessel Analyzer (Imedos, Jena, Germany) before (baseline) and 1 week and 1 month after administration of intravitreal ranibizumab. Investigations of RVO patients were compared to 11 eyes of age- and sex-matched control subjects. RESULTS In RVO patients, dynamic analysis showed a significant increase of mean venous dilation from +2.46% ± 1.03% at baseline to +3.96% ± 1.3% at 1 week (P = .001). At 1 week mean maximum venous and arterial dilations did not differ from those of control subjects. Static analysis showed a mean overall significant decrease of central retinal artery equivalent and central retinal vein equivalent from baseline to 1 week (from 174.8 ± 22.5 measurement units [MU] to 167.2 ± 26.7 MU [P = .04], and from 228.4 ± 20.7 MU to 217.3 ± 22.8 [P = .0002]). Mean central retinal artery equivalent in healthy control subjects was 175.9 ± 10.45 MU, not significantly different from baseline, week 1, and month 1 of RVO eyes. Conversely, mean central retinal vein equivalent was 195.5 ± 9.91 MU in healthy control subjects, significantly different from baseline, week 1, and month 1 of RVO eyes. CONCLUSIONS Using the Dynamic Vessel Analyzer in patients with RVO, we found that intravitreal ranibizumab increased vein dilation (dynamic analysis) and had a vasoconstrictive effect on both arteries and veins (static analysis).
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Affiliation(s)
- Federico Corvi
- Department of Ophthalmology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, University Vita-Salute San Raffaele, Milan, Italy
| | - Carlo La Spina
- Department of Ophthalmology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, University Vita-Salute San Raffaele, Milan, Italy
| | - Lucia Benatti
- Department of Ophthalmology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, University Vita-Salute San Raffaele, Milan, Italy
| | - Lea Querques
- Department of Ophthalmology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, University Vita-Salute San Raffaele, Milan, Italy
| | - Rosangela Lattanzio
- Department of Ophthalmology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, University Vita-Salute San Raffaele, Milan, Italy
| | - Francesco Bandello
- Department of Ophthalmology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, University Vita-Salute San Raffaele, Milan, Italy
| | - Giuseppe Querques
- Department of Ophthalmology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, University Vita-Salute San Raffaele, Milan, Italy; Department of Ophthalmology, University Paris Est Creteil, Centre Hospitalier Intercommunal de Creteil, Creteil, France.
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Nethi SK, Veeriah V, Barui AK, Rajendran S, Mattapally S, Misra S, Chatterjee S, Patra CR. Investigation of molecular mechanisms and regulatory pathways of pro-angiogenic nanorods. NANOSCALE 2015; 7:9760-9770. [PMID: 25963768 PMCID: PMC4724197 DOI: 10.1039/c5nr01327e] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Angiogenesis, a process involving the growth of new blood vessels from the pre-existing vasculature, plays a crucial role in various pathophysiological conditions. We have previously demonstrated that europium hydroxide [Eu(III)(OH)3] nanorods (EHNs) exhibit pro-angiogenic properties through the generation of reactive oxygen species (ROS) and mitogen activated protein kinase (MAPK) activation. Considering the enormous implication of angiogenesis in cardiovascular diseases (CVDs) and cancer, it is essential to understand in-depth molecular mechanisms and signaling pathways in order to develop the most efficient and effective alternative treatment strategy for CVDs. However, the exact underlying mechanism and cascade signaling pathways behind the pro-angiogenic properties exhibited by EHNs still remain unclear. Herein, we report for the first time that the hydrogen peroxide (H2O2), a redox signaling molecule, generated by these EHNs activates the endothelial nitric oxide synthase (eNOS) that promotes the nitric oxide (NO) production in a PI3K (phosphoinositide 3-kinase)/Akt dependent manner, eventually triggering angiogenesis. We intensely believe that the investigation and understanding of the in-depth molecular mechanism and signaling pathways of EHNs induced angiogenesis will help us in developing an effective alternative treatment strategy for cardiovascular related and ischemic diseases where angiogenesis plays an important role.
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Affiliation(s)
- Susheel Kumar Nethi
- Biomaterials Group, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, India
- Academy of Scientific and Innovative Research (AcSIR), 2 Rafi Marg, New Delhi, India
| | - Vimal Veeriah
- Vascular Biology Lab, Life Sciences Division, AU-KBC Research Centre, Anna University, Chennai, Tamil Nadu, India
| | - Ayan Kumar Barui
- Biomaterials Group, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, India
- Academy of Scientific and Innovative Research (AcSIR), 2 Rafi Marg, New Delhi, India
| | - Saranya Rajendran
- Vascular Biology Lab, Life Sciences Division, AU-KBC Research Centre, Anna University, Chennai, Tamil Nadu, India
| | - Saidulu Mattapally
- Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, India
| | - Sanjay Misra
- Vascular and Interventional Radiology Translational Laboratory, Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA
| | - Suvro Chatterjee
- Vascular Biology Lab, Life Sciences Division, AU-KBC Research Centre, Anna University, Chennai, Tamil Nadu, India
- Department of Biotechnology, Anna University, Chennai, India
| | - Chitta Ranjan Patra
- Biomaterials Group, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, India
- Academy of Scientific and Innovative Research (AcSIR), 2 Rafi Marg, New Delhi, India
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Cytokines, angiogenic, and antiangiogenic factors and bioactive lipids in preeclampsia. Nutrition 2015; 31:1083-95. [PMID: 26233865 DOI: 10.1016/j.nut.2015.03.013] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2014] [Revised: 03/07/2015] [Accepted: 03/19/2015] [Indexed: 02/03/2023]
Abstract
Preeclampsia is a low-grade systemic inflammatory condition in which oxidative stress and endothelial dysfunction occurs. Plasma levels of soluble receptor for vascular endothelial growth factor (VEGFR)-1, also known as sFlt1 (soluble fms-like tyrosine kinase 1), an antiangiogenic factor have been reported to be elevated in preeclampsia. It was reported that pregnant mice deficient in catechol-O-methyltransferase (COMT) activity show a preeclampsia-like phenotype due to a deficiency or absence of 2-methoxyoestradiol (2-ME), a natural metabolite of estradiol that is elevated during the third trimester of normal human pregnancy. Additionally, autoantibodies (AT1-AAs) that bind and activate the angiotensin II receptor type 1 a (AT1 receptor) also have a role in preeclampsia. None of these abnormalities are consistently seen in all the patients with preeclampsia and some of them are not specific to pregnancy. Preeclampsia could occur due to an imbalance between pro- and antiangiogenic factors. VEGF, an angiogenic factor, is necessary for the transport of polyunsaturated fatty acids (PUFAs) to endothelial cells. Hence reduced VEGF levels decrease the availability of PUFAs to endothelial cells. This leads to a decrease in the formation of anti-inflammatory and angiogenic factors: lipoxins, resolvins, protectins, and maresins from PUFAs. Lipoxins, resolvins, protectins, maresins, and PUFAs suppress insulin resistance; activation of leukocytes, platelets, and macrophages; production of interleukin-6 and tumor necrosis factor-α; and oxidative stress and endothelial dysfunction; and enhance production of prostacyclin and nitric oxide (NO). Estrogen enhances the formation of lipoxin A4 and NO. PUFAs also augment the production of NO and inhibit the activity of angiotensin-converting enzyme and antagonize the actions of angiotensin II. Thus, PUFAs can prevent activation of angiotensin II receptor type 1 a (AT1 receptor). Patients with preeclampsia have decreased plasma phospholipid concentrations of arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), the precursors of lipoxins (from AA), resolvins (from EPA and DHA), and protectins (from DHA) and prostaglandin E1 (PGE1 from DGLA: dihomo-γ-linolenic acid) and prostacyclin (PGI2 derived from AA). Based on these evidences, it is proposed that preeclampsia may occur due to deficiency of PUFAs and their anti-inflammatory products: lipoxins, resolvins, protectins, and maresins.
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Manresa N, Mulero J, Losada M, Zafrilla P. Influence of anti-VEGF about cardiovascular biomarkers in age related macular degeneration. J Nutr Health Aging 2015; 19:228-31. [PMID: 25651450 DOI: 10.1007/s12603-014-0531-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Systemic VEGF inhibition disrupts endothelial homeostasis and accelerates the atherogenesis, suggesting that these events contribute to the clinical cardiovascular adverse events of VEGF-inhibiting therapies. The objective of the current study was to analyze the effect of anti-VEGF therapy on cardiovascular risk factors in patients with exudative age related macular degeneration. A total of 73 patients with exudative age related macular degeneration (without previous anti-VEGF therapy) were treated with two anti-VEGF: Ranibizumab and Pegaptanib sodium. The follow up was 6 months. The following parameters were determined before and after treatment: homocysteine, lipids (total cholesterol, triglycerides, HDL-c, LDL-c), C-Reactive Protein and fibrinogen. There were not statistically significant differences in parameters studied before and after treatment with both Pegaptanib sodium and Ranibizumab, except C-Reactive Protein. Of all patients analyzed, only 3 of them have initially C-Reactive Protein levels above normal levels and after antiangiogenic therapy, there was a significant increase in C-Reactive Protein. We have not found results in our study who to suspect that treatment with anti-VEGF in the patients with exudative age related macular degeneration increases cardiovascular risk predictors. However, after therapy was increased the CRP and fibrinogen may mean that anti-VEGF contribute an alteration of endothelial homeostasis in exudative AMD.
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Affiliation(s)
- N Manresa
- N. Manresa, Department of Food Technology and Nutrition, Catholic University of San Antonio, Murcia 30107, Spain. , Phone: +34968278705, Fax: +34968278622
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Exercise training could improve age-related changes in cerebral blood flow and capillary vascularity through the upregulation of VEGF and eNOS. BIOMED RESEARCH INTERNATIONAL 2014; 2014:230791. [PMID: 24822184 PMCID: PMC4005099 DOI: 10.1155/2014/230791] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/21/2014] [Accepted: 03/24/2014] [Indexed: 11/30/2022]
Abstract
This study aimed to investigate the effect of exercise training on age-induced microvascular alterations in the brain. Additionally, the association with the protein levels of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) was also assessed. Male Wistar rats were divided into four groups: sedentary-young (SE-Young, n = 5), sedentary aged (SE-Aged, n = 8), immersed-aged (IM-Aged, n = 5), and exercise trained-aged (ET-Aged, 60 minutes/day and 5 days/week for 8 weeks, n = 8) rats. The MAPs of all aged groups, SE-Aged, IM-Aged, and ET-Aged, were significantly higher than that of the SE-Young group. The regional cerebral blood flow (rCBF) in the SE-Aged and IM-Aged was significantly decreased as compared to SE-Young groups. However, rCBF of ET-Aged group was significantly higher than that in the IM-Aged group (P < 0.05). Moreover, the percentage of capillary vascularity (%CV) and the levels of VEGF and eNOS in the ET-Aged group were significantly increased compared to the IM-Aged group (P < 0.05). These results imply that exercise training could improve age-induced microvascular changes and hypoperfusion closely associated with the upregulation of VEGF and eNOS.
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Shahin M, Gad MA, Hamza W. Impact of intravitreal triamcinolone acetonide versus intravitreal bevacizumab on retrobulbar hemodynamic in patients with diabetic macular edema. Cutan Ocul Toxicol 2013; 33:49-53. [PMID: 23742103 DOI: 10.3109/15569527.2013.796478] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
PURPOSE To evaluate and compare retrobulbar hemodynamic changes measured with color Doppler imaging (CDI) in diabetic patients receiving intravitreal triamcinolone acetonide (IVTA) versus bevacizumab. METHODS Patients with diffuse diabetic macular edema were assessed prospectively by CDI following intravitreal injection of triamcinolone acetonide (group I, 12 eyes) versus bevacizumab (group II, 14 eyes). CDI was used to measure the peak systolic velocity (PSV), end diastolic velocity (EDV) and the resistive index (RI) of the central retinal artery (CRA), ophthalmic artery (OA) and posterior ciliary arteries (PCA) one day preoperatively and one week postoperatively. RESULTS In group I, EDV of OA and CRA decreased significantly (p = 0.007 and 0.018, respectively). The PSV and RI of PCA decreased significantly (p = 0.035 and 0.002, respectively). In group II, both the PSV and EDV of the CRA decreased significantly (p = 0.000). Comparing the percentage of change in both groups, PSV of the CRA decreased significantly in group II (p = 0.034), while IVTA has more significant effect on the ophthalmic artery hemodynamic parameters as EDV decreased and RI increased significantly (p = 0.045 and 0.043, respectively) CONCLUSION Intravitreal injections of triamcinolone acetonide and bevacizumab have a significant effect on the ocular hemodynamic. The effect of bevacizumab is statistically significant on the PSV of CRA compared to IVTA.
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Affiliation(s)
- Maha Shahin
- Department of Ophthalmology, Faculty of Medicine, Mansoura University , Mansoura , Egypt and
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Mendrinos E, Mangioris G, Papadopoulou DN, Donati G, Pournaras CJ. Long-term results of the effect of intravitreal ranibizumab on the retinal arteriolar diameter in patients with neovascular age-related macular degeneration. Acta Ophthalmol 2013; 91:e184-90. [PMID: 23590391 DOI: 10.1111/aos.12008] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
PURPOSE To study the effect of intravitreal (IVT) ranibizumab on the retinal arteriolar diameter in patients with neovascular age-related macular degeneration (AMD). METHODS Ten eyes of 10 patients with previously untreated neovascular AMD were included. All eyes had three monthly IVT injections of ranibizumab and then were retreated as needed, based on visual acuity and optical coherence tomography (OCT) criteria. The diameter of the retinal arterioles was measured in vivo with a retinal vessel analyser (RVA) before the first IVT injection, 7 and 30 days after the first, the second and the third injection, and at month 12 of follow-up. RESULTS A significant vasoconstriction of the retinal arterioles was observed following each one of the first three IVT injections of ranibizumab. Thirty days following the first, second and third injection, there was a mean decrease of 8.4 ± 3.2%, 11.9 ± 4.5% and 18.5 ± 7.2%, respectively, of the retinal arteriolar diameter compared with baseline (p < 0.01). At month 12, the vasoconstriction was still present with a mean decrease of 19.1 ± 8.3% of the retinal arteriolar diameter compared with baseline (p < 0.01). Median number of ranibizumab injections was 4 (range 3-10). There was no correlation between the number of injections and percentage diameter decrease at month 12 (r = -0.54, p > 0.1). There was no significant change in mean arterial pressure (MAP) during the period of follow-up (p > 0.05). CONCLUSIONS These results suggest that IVT ranibizumab induces sustained retinal arteriolar vasoconstriction in eyes with neovascular AMD.
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Affiliation(s)
- Efstratios Mendrinos
- Vitreo-retinal Unit, Department of Ophthalmology, Faculty of Medicine, Geneva University Hospitals, University of Geneva, Geneva, Switzerland
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Therapeutic neovascularization for coronary disease: current state and future prospects. Basic Res Cardiol 2011; 106:897-909. [DOI: 10.1007/s00395-011-0200-1] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2011] [Revised: 06/01/2011] [Accepted: 06/17/2011] [Indexed: 12/19/2022]
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Tolentino M. Systemic and Ocular Safety of Intravitreal Anti-VEGF Therapies for Ocular Neovascular Disease. Surv Ophthalmol 2011; 56:95-113. [DOI: 10.1016/j.survophthal.2010.08.006] [Citation(s) in RCA: 204] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2009] [Revised: 08/25/2010] [Accepted: 08/31/2010] [Indexed: 01/11/2023]
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Abstract
PURPOSE The purpose of this study was to determine the histopathologic characteristics of bevacizumab-treated human proliferative diabetic retinopathy (PDR) membranes with particular regard to membrane vasculature as a step toward addressing the effects of the drug on PDR membranes. Intravitreous injection of bevacizumab, an antivascular endothelial growth factor monoclonal antibody, has recently been advocated as an adjunct in surgery for PDR. In this context, a clinically observed decrease in PDR epiretinal membrane vascularity (vascular regression) occurs from 24 hours to 48 hours after injection, but the exact mechanisms of drug action are unknown. METHODS A consecutive series of seven PDR membrane specimens that had been removed sequentially from seven bevacizumab-treated patients were studied retrospectively. The membrane specimens were examined using light microscopic methods, including immunohistochemistry. RESULTS Five of the seven membranes were clinically avascular (one contained "ghost" vessels) and did not hemorrhage during excision. Of these 5 specimens, which included 1 removed 7 days after a total of 6 intravitreous injections of 1.25 mg bevacizumab, 4 contained histologically detectable capillaries (1 did not). These blood vessels were lined by endothelial cells as determined by immunohistochemistry for the endothelial markers CD31 and CD34. The two remaining membranes were clinically and histologically still vascularized despite bevacizumab treatment. All the specimens also contained smooth muscle actin-containing fibroblastic cells within the collagenous stroma. CONCLUSION The findings do not support the concept that the clinical phenomenon of vascular regression in PDR membranes after bevacizumab injection in the vitreous is resulting from obliteration of the membrane blood vessels. Another mechanism appears to be involved in at least some patients, possibly a vasoconstrictive response. Such a mechanism might explain reversal of the effects of bevacizumab that has been reported after this treatment.
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Friberg TR, Tolentino M, Weber P, Patel S, Campbell S, Goldbaum M. Pegaptanib sodium as maintenance therapy in neovascular age-related macular degeneration: the LEVEL study. Br J Ophthalmol 2010; 94:1611-7. [PMID: 20472746 PMCID: PMC2991041 DOI: 10.1136/bjo.2009.174946] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Aim To assess the efficacy of pegaptanib as maintenance therapy in neovascular age-related macular degeneration (NV-AMD) patients after induction therapy. Methods A phase IV, prospective, open-label, uncontrolled exploratory study including subjects with subfoveal NV-AMD who had had one to three induction treatments 30–120 days before entry and showed investigator-determined clinical/anatomical NV-AMD improvement. Lesions in the study eye were: any subtype, 12 or fewer disc areas; postinduction centre point thickness (CPT) 275 μm or less or thinning of 100 μm or more (optical coherence tomography); visual acuity (VA) 20/20–20/400. Intravitreal pegaptanib 0.3 mg was administered as maintenance every 6 weeks for 48 weeks with follow-up to week 54. Booster treatment additional unscheduled treatment for wet age-related macular degeneration, was allowed in the study eye at the investigators' discretion for clinical deterioration. Results Of 568 enrolled subjects, 86% completed 1 year of pegaptanib. Mean VA improvement during induction (49.6 to 65.5 letters) was well preserved (54-week mean 61.8 letters). Mean CPT was relatively stable during maintenance (20 μm increase during the study). Fifty per cent did not receive unscheduled booster treatment to week 54; 46% did have one such booster (mean 147 days after maintenance initiation). Conclusions An induction-maintenance strategy, using non-selective then selective vascular endothelial growth factor (VEGF) inhibitors, could be considered for NV-AMD. This approach may have particular relevance for patients with systemic comorbidities who require long-term anti-VEGF therapy for NV-AMD.
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Affiliation(s)
- Thomas R Friberg
- Ophthalmology, University of Pittsburgh Medical Center Eye Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
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Abstract
Angiogenesis is the formation of new blood vessels from pre-existing vasculature. Pathologic angiogenesis in the eye can lead to severe visual impairment. In our review, we discuss the roles of both pro-angiogenic and anti-angiogenic molecular players in corneal angiogenesis, proliferative diabetic retinopathy, exudative macular degeneration and retinopathy of prematurity, highlighting novel targets that have emerged over the past decade.
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Affiliation(s)
- Yureeda Qazi
- Department of Ophthalmology, John Moran Eye Center, University of Utah, Salt Lake City, UT-84132, USA
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Boodhwani M, Sellke FW. Therapeutic angiogenesis in diabetes and hypercholesterolemia: influence of oxidative stress. Antioxid Redox Signal 2009; 11:1945-59. [PMID: 19187003 PMCID: PMC2848518 DOI: 10.1089/ars.2009.2439] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Despite significant improvements in the medical, percutaneous, and surgical management, numerous patients are first seen with non-revascularizable coronary artery disease (CAD). The growth of new blood vessels to improve myocardial perfusion (i.e., therapeutic angiogenesis) is an attractive treatment option for these patients. However, the successes of angiogenic therapy, observed in preclinical studies, have not been realized in clinical trials. Increasing evidence suggests that this discrepancy between animal and human studies may be due to the nature of the substrate, or the molecular and cellular environment within which the angiogenic agent acts. Antiangiogenic influences, including endothelial dysfunction, hypercholesterolemia, and diabetes, are present in virtually all patients with advanced CAD. Recent studies have better characterized the abnormalities associated with these disease states, providing novel targets for intervention. These substrate-modifying interventions can potentially enhance the response to protein-, gene-, or cell-based angiogenic therapy. In this review, we discuss key aspects of the angiogenic process and the pathophysiologic and molecular mechanisms that contribute to an impaired angiogenic response in the setting of endothelial dysfunction, hypercholesterolemia, and diabetes, with a focus on the role of oxidative stress. Last, we briefly explore substrate modifying agents that have been evaluated in preclinical and clinical studies to improve the angiogenic response.
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Affiliation(s)
- Munir Boodhwani
- Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, Canada
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Papadopoulou DN, Mendrinos E, Mangioris G, Donati G, Pournaras CJ. Intravitreal ranibizumab may induce retinal arteriolar vasoconstriction in patients with neovascular age-related macular degeneration. Ophthalmology 2009; 116:1755-61. [PMID: 19560206 DOI: 10.1016/j.ophtha.2009.03.017] [Citation(s) in RCA: 101] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2008] [Revised: 03/11/2009] [Accepted: 03/11/2009] [Indexed: 10/20/2022] Open
Abstract
OBJECTIVE To study the effect of intravitreal (IVT) ranibizumab (Lucentis; Genentech, Inc, San Francisco, CA) on the retinal arteriolar diameter in patients with neovascular age-related macular degeneration (AMD). DESIGN Prospective consecutive interventional case series. PARTICIPANTS Eleven eyes of eleven patients with previously untreated neovascular AMD. METHODS All eyes had 3 monthly IVT injections of ranibizumab. The diameter of the retinal arterioles was measured in vivo with a retinal vessel analyzer (RVA) before the first IVT injection and then 7 and 30 days after the first, second, and third injections. MAIN OUTCOME MEASURES Primary end points were changes in retinal arteriolar diameter and mean arterial pressure (MAP) after IVT ranibizumab. Secondary end points were changes in best-corrected visual acuity (BCVA), central retinal thickness, and intraocular pressure after IVT ranibizumab, and appearance of adverse events during the follow-up period. RESULTS A significant decrease of the retinal arteriolar diameter was observed after each IVT injection of ranibizumab. Thirty days after the first, second, and third injections, there was a mean decrease of 8.1+/-3.2%, 11.5+/-4.4%, and 17.6+/-7.4%, respectively, of the retinal arteriolar diameter compared with baseline values (P<0.01). There was no significant change in MAP during the period of follow-up (P>0.05). Thirty days after the third IVT injection of ranibizumab, mean BCVA improved by 6.5+/-4.9 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, and central retinal thickness decreased by 91+/-122 microm (P = 0.03). CONCLUSIONS These results suggest that IVT ranibizumab may induce retinal arteriolar vasoconstriction in patients with neovascular AMD after IVT ranibizumab. Further studies evaluating larger sample sizes are needed to confirm these results and potential adverse effects on the retinal circulation in patients with AMD and retinal vascular diseases. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.
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Affiliation(s)
- Domniki N Papadopoulou
- Vitreo-retinal Unit, Department of Ophthalmology, 22 rue Alcide Jentzer, Geneva, Switzerland
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Effects of photodynamic therapy on subfoveal blood flow in neovascular age-related macular degeneration patients. Eye (Lond) 2009; 24:706-12. [DOI: 10.1038/eye.2009.130] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
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Abstract
This article reviews current efforts to make glucose sensors based on the inherent optical properties of single walled carbon nanotubes. The advantages of single walled carbon nanotubes over traditional organic and nanoparticle fluorophores for in vivo-sensing applications are discussed. Two recent glucose sensors made by our group are described, with the first being an enzyme-based glucose sensor that couples a reaction mediator, which quenches nanotube fluorescence, on the surface of the nanotube with the reaction of the enzyme. The second sensor is based on competitive equilibrium binding between dextran-coated nanotubes and concanavalin A. The biocompatibility of a model sensor is examined using the chicken embryo chorioallantoic membrane as a tissue model. The advantages of measuring glucose concentration directly, like most optical sensors, versus measuring the flux in glucose concentration, like most electrochemical sensors, is discussed.
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Affiliation(s)
- Paul W Barone
- Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
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Corbin KD, Pendleton LC, Solomonson LP, Eichler DC. Phosphorylation of argininosuccinate synthase by protein kinase A. Biochem Biophys Res Commun 2008; 377:1042-6. [PMID: 18948083 DOI: 10.1016/j.bbrc.2008.10.056] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2008] [Accepted: 10/09/2008] [Indexed: 10/21/2022]
Abstract
Argininosuccinate synthase (AS) is essential for endothelial nitric oxide (NO) production and its regulation in this capacity has been studied primarily at the transcriptional level. The dynamics of vascular function suggest that an acute regulation system may mediate AS function. This premise underlies our hypothesis that AS is phosphorylated in vascular endothelium. Immunoprecipitation and immobilized metal affinity chromatography demonstrated that AS is an endogenous phosphoprotein. An in vitro kinase screen revealed that protein kinase A (PKA), a kinase that enhances NO production via eNOS activation, phosphorylated AS. Vascular endothelial growth factor (VEGF) was identified as a candidate pathway for regulating AS phosphorylation since it enhanced NO production and activated PKA and eNOS. MDLA, an AS inhibitor, diminished maximal VEGF-mediated NO production. In addition, immunoprecipitation studies suggested that VEGF enhanced AS phosphorylation. Overall, these results represent the first demonstration that vascular endothelial NO production can be regulated by dynamic AS phosphorylation.
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Affiliation(s)
- Karen D Corbin
- Department of Molecular Medicine, College of Medicine, University of South Florida, 12901 Bruce B. Downs Boulevard, MDC Box 7, Tampa, FL 33612, USA
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Abstract
Since nitric oxide (NO) was identified as the endothelial-derived relaxing factor in the late 1980s, many approaches have attempted to provide an adequate means for measuring physiological levels of NO. Although several techniques have been successful in achieving this aim, the electrochemical method has proved the only technique that can reliably measure physiological levels of NO in vitro, in vivo, and in real time. We describe here the development of electrochemical sensors for NO, including the fabrication of sensors, the detection principle, calibration, detection limits, selectivity, and response time. Furthermore, we look at the many experimental applications where NO selective electrodes have been successfully used.
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Affiliation(s)
- Ian R Davies
- World Precision Instruments Limited, Aston, United Kingdom
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Doblas S, Saunders D, Kshirsagar P, Pye Q, Oblander J, Gordon B, Kosanke S, Floyd RA, Towner RA. Phenyl-tert-butylnitrone induces tumor regression and decreases angiogenesis in a C6 rat glioma model. Free Radic Biol Med 2008; 44:63-72. [PMID: 18045548 DOI: 10.1016/j.freeradbiomed.2007.09.006] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2007] [Revised: 09/07/2007] [Accepted: 09/10/2007] [Indexed: 11/23/2022]
Abstract
The prognosis of patients who are diagnosed with glioblastoma multiforme is very poor, due to the difficulty of an early and accurate diagnosis and the lack of currently efficient therapeutic compounds. The efficacy of phenyl-tert-butylnitrone (PBN) as a potential anti-glioma therapeutic drug was assessed by magnetic resonance (MR) imaging (T(1)/T(2)-weighted imaging) and MR angiography (time-of-flight imaging, in conjunction with a Mathematica-based program) methods by monitoring morphologic properties, growth patterns, and angiogenic behaviors of a moderately aggressive rat C6 glioma model. MR results from untreated rats showed the diffusive invasiveness of C6 gliomas, with some associated angiogenesis. PBN administration as a pretreatment was found to clearly induce a decrease in growth rate and tumor regression as well as preventing angiogenesis. This compound even had a 40% efficiency in reducing well-established tumors. MR findings rivaled those from histology and angiogenesis marker immunostaining evaluations. In this study we demonstrated the efficiency of PBN as a potential anti-glioma drug and found it to inhibit tumor cell proliferation and prevent vascular alterations in early stages of glioma progression. The MR methods that we used also proved to be particularly suitable in following the angiogenic behavior and treatment response of a potential anti-glioma agent in a rat C6 glioma model.
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Affiliation(s)
- Sabrina Doblas
- Oklahoma University Bioengineering Center, Norman, OK, USA
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Zhang HY, Han DW, Su AR, Zhang LT, Zhao ZF, Ji JQ, Li BH, Ji C. Intestinal endotoxemia plays a central role in development of hepatopulmonary syndrome in a cirrhotic rat model induced by multiple pathogenic factors. World J Gastroenterol 2007; 13:6385-95. [PMID: 18081228 PMCID: PMC4205458 DOI: 10.3748/wjg.v13.i47.6385] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To characterize the correlation between severity of hepatopulmonary syndrome (HPS) and degree of hepatic dysfunction, and to explore how intestinal endotoxemia (IETM) affects the development of HPS in cirrhotic rats.
METHODS: Male Wister rats were fed with a diet containing maize flour, lard, cholesterol, and alcohol and injected subcutaneously with CCl4 oil solution every two days for 8 wk to induce typical cirrhosis and development of HPS. The animals were also given a nitric oxide (NO) production inhibitor, Nω-nitro-L-arginine methyl ester (L-NAME) intraperitoneally, and an iNOS inhibitor, aminoguanidine hydrochloride (AG) via gavage daily from the end of the 4th wk to the end of the 6th or 8th wk, or a HO-1 inhibitor, zinc protoporphyrin (ZnPP) intraperitoneally 12 h prior to killing. Blood, liver and lung tissues were sampled.
RESULTS: Histological deterioration of the lung paralleled to that of the liver in the cirrhotic rats. The number of pulmonary capillaries was progressively increased from 6.1 ± 1.1 (count/filed) at the 4th wk to 14.5 ± 2.4 (count/filed) at the 8th wk in the cirrhotic rats. Increased pulmonary capillaries were associated with increased blood levels of lipopolysaccharide (LPS) (0.31 ± 0.08 EU/mL vs control 0.09 ± 0.03 EU/mL), alanine transferase (ALT, 219.1 ± 17.4 U/L vs control 5.9 ± 2.2 U/L) and portal vein pressure. Compared with normal control animals, the number of total cells in bronchoalveolar lavage fluid (BALF) of the cirrhotic rats at the 8th wk was not changed, but the number of macrophages and the ratio of macrophages to total cells were increased by nearly 2-fold, protein expression of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) started to increase significantly at the 4th wk, and reached its peak at the 8th wk in the lung of cirrhotic rats. The increase of iNOS expression appeared to be quicker than that of eNOS. NO2-/NO3- was also increased, which was correlated to the increase of iNOS (r = 0.7699, P < 0.0001) and eNOS (r = 0.5829, P < 0.002). mRNA expression of eNOS and iNOS was highly consistent with their protein expression.
CONCLUSION: Progression and severity of HPS as indicated by both increased pulmonary capillaries and histological changes are closely associated with LPS levels and progression of hepatic dysfunction as indicated by increased levels of ALT and portal vein pressure. Intestinal endotoxemia plays a central role in the development of HPS in the cirrhotic rat model by inducing NO and/or CO.
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Abstract
Vascular endothelial growth factor (VEGF) is a central regulator of both physiological and pathological angiogenesis. Pegaptanib, a 28-nucleotide RNA aptamer specific for the VEGF(165) isoform, binds to it in the extracellular space, leaving other isoforms unaffected, and inhibits such key VEGF actions as promotion of endothelial cell proliferation and survival, and vascular permeability. Pegaptanib already has been examined as a treatment for two diseases associated with ocular neovascularization, age-related macular degeneration (AMD) and diabetic macular edema (DME). Preclinical studies have shown that VEGF(165) alone mediates pathological ocular neovascularization and that its inactivation by pegaptanib inhibits the choroidal neovascularization observed in patients with neovascular AMD. In contrast, physiological vascularization, which is supported by the VEGF(121) isoform, is unaffected by this inactivation of VEGF(165). In addition, animal model studies have shown that intravitreous injection of pegaptanib can inhibit the breakdown of the blood-retinal barrier characteristic of diabetes and even can reverse this damage to some degree. These preclinical findings formed the basis for randomized controlled trials examining the efficacy of pegaptanib as a therapy for AMD and DME. The VEGF Inhibition Study in Ocular Neovascularization (VISION) trial comprising two replicate, pivotal phase 3 studies, demonstrated that intravitreous injection of pegaptanib resulted in significant clinical benefit, compared with sham injection, for all prespecified clinical end points, irrespective of patient demographics or angiographic subtype, and led to pegaptanib's approval as a treatment for AMD. A phase 2 trial has provided support for the efficacy of intravitreous pegaptanib in the treatment of DME.
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Tsai DC, Charng MJ, Lee FL, Hsu WM, Chen SJ. Different Plasma Levels of Vascular Endothelial Growth Factor and Nitric Oxide between Patients with Choroidal and Retinal Neovascularization. Ophthalmologica 2006; 220:246-51. [PMID: 16785756 DOI: 10.1159/000093079] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2005] [Accepted: 11/04/2005] [Indexed: 11/19/2022]
Abstract
Because the blood flow is much more intense in the choroid than in the retina, it is interesting to explore whether choroidal neovascularization (CNV) is more influenced by plasma angiogenic factors than retinal neovascularization. The aim of this study was to investigate plasma profiles of vascular endothelial growth factor (VEGF) and nitric oxide (NO) in patients with CNV due to age-related macular degeneration (AMD) and in those with retinal neovascularization due to proliferative diabetic retinopathy (PDR). Seventy-seven subjects with AMD, 22 with PDR, and 42 nondiabetic, non-AMD controls were enrolled in this comparative case series. AMD subjects were classified into three groups: dry type (dry AMD, n = 17), wet type with active CNV (CNV/AMD, n = 42), and disciform scar due to advanced wet AMD (scar/AMD, n = 18). Plasma VEGF and NO levels of each subject were measured with enzyme-linked immunosorbent assay and chemiluminescence, respectively. Plasma VEGF level in CNV/AMD (median 256.0 pg/ml, interquartile range 146.4-375.3 pg/ml) was significantly higher than in PDR (124.8 pg/ml, 75.7-215.3 pg/ml; p = 0.004) and controls (120.3 pg/ml, 82.8-168.2 pg/ml, p =0.001). CNV/AMD also had the highest VEGF level among the AMD subgroups. Plasma NO level was significantly elevated in PDR (137.4 microM, 63.7-240.1 microM) when compared with CNV/AMD (71.8 microM, 42.4-113.3 microM; p = 0.004) and controls (62.6 microM, 39.0-114.9 microM; p = 0.002). There was no significant difference in NO levels among the AMD subgroups. No significant correlation between VEGF and NO levels was noted. These findings indicate that both circulating VEGF and NO may play different roles in the pathogenesis of retinal neovascularization and CNV.
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Affiliation(s)
- Der-Chong Tsai
- Department of Ophthalmology, Taipei Veterans General Hospital and National Yang-Ming University, Taipei, Taiwan, ROC
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Jacobs ER, Zhu D, Gruenloh S, Lopez B, Medhora M. VEGF-induced relaxation of pulmonary arteries is mediated by endothelial cytochrome P-450 hydroxylase. Am J Physiol Lung Cell Mol Physiol 2006; 291:L369-77. [PMID: 16679379 DOI: 10.1152/ajplung.00265.2004] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The cytochrome P-450 metabolite 20-HETE induces calcium-, endothelial-, and nitric oxide (NO)-dependent relaxation of bovine pulmonary arteries (PA). VEGF is an NO-dependent dilator of systemic arteries and plays a key role in maintaining the integrity of the pulmonary vasculature. We tested the effect of VEGF on PA diameter and tone and the contribution of cytochrome P-450 family 4 (CYP4) to vasoactive effects of VEGF. Bovine PA rings (1 mm in diameter) relaxed with VEGF (0.1-10 nM) in an endothelial- and eNOS-dependent manner. This response was blunted by pretreatment with the CYP4 inhibitor dibromododecynyl methyl sulfonamide (DDMS) as well as a mechanistically different CYP4 inhibitor N-hydroxy-N'-(4-butyl-2-methylphenyl)formamidine. PAs also increased in diameter by 6-12% in the presence of VEGF (10 nM), and this increase was attenuated by DDMS. In contrast to that shown in PAs, 20-HETE constricted bovine renal arteries and did not increase intracellular Ca(2+) in renal artery endothelial cells as observed in bovine pulmonary artery endothelial cells (BPAECs). VEGF-evoked increases in intracellular Ca(2+) concentration ([Ca(2+)](i)) in BPAECs were blunted by treatment with DDMS. Both VEGF (10 nM) and 20-HETE (1-5 microM) stimulated NO release from cultured BPAECs, and once again VEGF-induced increases were attenuated by pretreating the cells with DDMS. We conclude that CYP4/20-HETE contributes to VEGF-stimulated NO release and vasodilation in bovine PAs. Given the unique expression of 20-HETE-forming CYP4 in BPAECs vs. systemic arterial endothelial cells, CYP4 may be an important mediator of endothelial-dependent vasoreactivity in PAs.
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Affiliation(s)
- Elizabeth R Jacobs
- Cardiovascular Center, Pulmonary and Critical Care Division, Department of Medicine, Medical College of Wisconsin, Milwaukee, 53226, USA.
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Liu X, Liu Q, Gupta E, Zorko N, Brownlee E, Zweier JL. Quantitative measurements of NO reaction kinetics with a Clark-type electrode. Nitric Oxide 2005; 13:68-77. [PMID: 15964224 DOI: 10.1016/j.niox.2005.04.011] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2005] [Revised: 04/26/2005] [Accepted: 04/30/2005] [Indexed: 11/23/2022]
Abstract
Nitric oxide (NO) plays important physiological roles in the body. Knowledge regarding the kinetics of NO catabolism is important for understanding the biological functions of NO. Clark-type NO electrodes have been frequently employed in measuring the kinetics of NO reactions; however, the slow response time of these electrodes can cause measurement errors and limit the application of the electrode in measurements of fast NO reactions. In this study, a simplified diffusion model is given for describing the response process of the NO electrode to the change of NO concentration. The least-square method is used in fitting the currents calculated from the diffusion equation to the experimental curves for determining the diffusion parameters and rate constants. The calculated currents are in excellent accordance with the experimental curves for different NO reaction kinetics. It has been demonstrated that when using an NO electrode with a response time of approximately 6 s to measure fast NO reactions with a half-life of approximately 1s, the response currents of the electrode have large differences compared to the curve of actual NO concentration in the solution; however, the rate constant of NO decay can still be accurately determined by computer simulations with the simplified diffusion model. Theoretical analysis shows that an NO electrode with a response time of 6 s (D/L2=0.06 s-1) and the lowest detection limit of 1 nM NO can be used in measuring kinetics of extremely rapid NO reactions with a half-life below 10 ms.
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Affiliation(s)
- Xiaoping Liu
- Davis Heart and Lung Research Institute and Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
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Abstract
The incidence of diabetic retinopathy is still increasing in developed countries. Tight glycemic control and laser therapy reduce vision loss and blindness, but do not reverse existing ocular damage and only slow the progression of the disease. New pharmacologic agents that are currently under development and are specifically directed against clearly defined biochemical targets (i.e. aldose reductase inhibitors and protein kinase C-beta inhibitors) have failed to demonstrate significant efficacy in the treatment of diabetic retinopathy in clinical trials. In contrast, calcium dobesilate (2,5-dihydroxybenzenesulfonate), which was discovered more than 40 years ago and is registered for the treatment of diabetic retinopathy in more than 20 countries remains, to our knowledge, the only angioprotective agent that reduces the progression of this disease. An overall review of published studies involving calcium dobesilate (CLS 2210) depicts a rather 'non-specific' compound acting moderately, but significantly, on the various and complex disorders that contribute to diabetic retinopathy. Recent studies have shown that calcium dobesilate is a potent antioxidant, particularly against the highly damaging hydroxyl radical. In addition, it improves diabetic endothelial dysfunction, reduces apoptosis, and slows vascular cell proliferation.
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Affiliation(s)
- Ricardo P Garay
- Equipe d'Accueil EA2381, Laboratoire Pharmacologie Transports Ioniques Membranaires, Université Paris 7, Paris, France.
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Carvalho FA, Martins-Silva J, Saldanha C. Amperometric measurements of nitric oxide in erythrocytes. Biosens Bioelectron 2004; 20:505-8. [PMID: 15494232 DOI: 10.1016/j.bios.2004.02.015] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2004] [Revised: 02/22/2004] [Accepted: 02/23/2004] [Indexed: 11/18/2022]
Abstract
In the recent years, there has been an increase in the development of new biosensors that could be helpful in the study of various physiological processes. In this study, we report the development of a new in vitro experimental design for real-time nitric oxide (NO) amperometric measurements in erythrocyte suspensions. To achieve this, we employed human erythrocyte suspensions in sodium chloride 0.9%, pH 7 (haematocrit 0.05%). The production of NO by erythrocytes was measured with a commercial NO sensor during stimulation by L-arginine, acetylcholine, choline, atropine and velnacrine maleate (10 microM of final concentrations). We also measured the nitrite and nitrate concentrations produced by erythrocyte suspensions stimulated with the above effectors by means of the Griess reaction method. We observed that there was a direct relation between the electric current produced by the NO sensor, and the NO standard concentrations, thereby leading to a good calibration curve. The in vitro erythrocytes produced significant amperometric NO values in response to a wide range of effectors and these results have the same variation profile of the nitrites and nitrates results achieved with the Griess method. In conclusion, the amperometric NO sensor constitutes a reliable method for direct, and real-time measurement in vitro of the NO production of erythrocyte suspensions, As such, it offers a potential diagnostic technique for the evaluation of diseases, and the therapeutic progression of diseases, related to intracellular NO metabolism.
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Affiliation(s)
- Filomena A Carvalho
- Instituto de Bioquímica, Faculdade de Medicina de Lisboa, Unidade de Biopatologia Vascular, Instituto de Medicina Molecular, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal.
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Ambati J, Ambati BK, Yoo SH, Ianchulev S, Adamis AP. Age-related macular degeneration: etiology, pathogenesis, and therapeutic strategies. Surv Ophthalmol 2003; 48:257-93. [PMID: 12745003 DOI: 10.1016/s0039-6257(03)00030-4] [Citation(s) in RCA: 631] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Age-related macular degeneration is the principal cause of registered legal blindness among those aged over 65 in the United States, western Europe, Australia, and Japan. Despite intensive research, the precise etiology of molecular events that underlie age-related macular degeneration is poorly understood. However, investigations on parallel fronts are addressing this prevalent public health problem. Sophisticated biochemical and biophysical techniques have refined our understanding of the pathobiology of drusen, geographic atrophy, and retinal pigment epithelial detachments. Epidemiological identification of risk factors has facilitated an intelligent search for underlying mechanisms and fueled clinical investigation of behavior modification. Gene searches have not only brought us to the cusp of identifying the culpable gene loci in age-related macular degeneration, but also localized genes responsible for other macular dystrophies. Recent and ongoing investigations, often cued by tumor biology, have revealed an important role for various growth factors, particularly in the neovascular form of the condition. Transgenic and knockout studies have provided important mechanistic insights into the development of choroidal neovascularization, the principal cause of vision loss in age-related macular degeneration. This in turn has culminated in preclinical and clinical trials of directed molecular interventions.
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Affiliation(s)
- Jayakrishna Ambati
- Ocular Angiogenesis Laboratory, Department of Ophthalmology, University of Kentucky, Lexington, USA
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