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Article ; Online: Sublytic membrane-attack-complex (MAC) activation alters regulated rather than constitutive vascular endothelial growth factor (VEGF) secretion in retinal pigment epithelium monolayers.

Kunchithapautham, Kannan / Rohrer, Bärbel

2011 Volume 286, Issue 27, Page(s) 23717–23724

Abstract: Uncontrolled activation of the alternative complement pathway and secretion of vascular endothelial growth factor (VEGF) are thought to be associated with age-related macular degeneration (AMD). Previously, we have shown that in RPE monolayers, oxidative- ...

Abstract	Uncontrolled activation of the alternative complement pathway and secretion of vascular endothelial growth factor (VEGF) are thought to be associated with age-related macular degeneration (AMD). Previously, we have shown that in RPE monolayers, oxidative-stress reduced complement inhibition on the cell surface. The resulting increased level of sublytic complement activation resulted in VEGF release, which disrupted the barrier facility of these cells as determined by transepithelial resistance (TER) measurements. Induced rather than basal VEGF release in RPE is thought to be controlled by different mechanisms, including voltage-dependent calcium channel (VDCC) activation and mitogen-activated protein kinases. Here we examined the potential intracellular links between sublytic complement activation and VEGF release in RPE cells challenged with H(2)O(2) and complement-sufficient normal human serum (NHS). Disruption of barrier function by H(2)O(2) + NHS rapidly increased Ras expression and Erk and Src phosphorylation, but had no effect on P38 phosphorylation. Either treatment alone had little effect. TER reduction could be attenuated by inhibiting Ras, Erk and Src activation, or blocking VDCC or VEGF-R2 activation, but not by inhibiting P38. Combinatorial analysis of inhibitor effects demonstrated that sublytic complement activation triggers VEGF secretion via two pathways, Src and Ras-Erk, with the latter being amplified by VEGF-R2 activation, but has no effect on constitutive VEGF secretion mediated via P38. Finally, effects on TER were directly correlated with release of VEGF; and sublytic MAC activation decreased levels of zfp36, a negative modulator of VEGF transcription, resulting in increased VEGF expression. Taken together, identifying how sublytic MAC induces VEGF expression and secretion might offer opportunities to selectively inhibit pathological VEGF release only.
MeSH term(s)	Calcium Channels/metabolism ; Cell Line ; Complement Activation/drug effects ; Complement Activation/physiology ; Complement Membrane Attack Complex/metabolism ; Gene Expression Regulation/drug effects ; Gene Expression Regulation/physiology ; Humans ; Hydrogen Peroxide/pharmacology ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Oxidants/pharmacology ; Retinal Pigment Epithelium/cytology ; Retinal Pigment Epithelium/metabolism ; Tristetraprolin/biosynthesis ; Vascular Endothelial Growth Factor A/metabolism ; ras Proteins/biosynthesis ; src-Family Kinases/biosynthesis
Chemical Substances	Calcium Channels ; Complement Membrane Attack Complex ; Oxidants ; Tristetraprolin ; VEGFA protein, human ; Vascular Endothelial Growth Factor A ; ZFP36 protein, human ; Hydrogen Peroxide (BBX060AN9V) ; src-Family Kinases (EC 2.7.10.2) ; Mitogen-Activated Protein Kinase Kinases (EC 2.7.12.2) ; ras Proteins (EC 3.6.5.2)
Language	English
Publishing date	2011-05-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M110.214593
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Article: Prolonged SRC kinase activation, a mechanism to turn transient, sublytic complement activation into a sustained pathological condition in retinal pigment epithelium cells.

Rohrer, Bärbel / Kunchithapautham, Kannan / Genewsky, Andreas / Strauß, Olaf

Advances in experimental medicine and biology

2014 Volume 801, Page(s) 221–227

Abstract: Age-related macular degeneration (AMD) is a slowly progressing multifactorial disease involving genetic abnormalities and environmental insults. Genetic studies have demonstrated that polymorphisms in different complement proteins increase the risk for ... ...

Abstract	Age-related macular degeneration (AMD) is a slowly progressing multifactorial disease involving genetic abnormalities and environmental insults. Genetic studies have demonstrated that polymorphisms in different complement proteins increase the risk for developing AMD. Previously, we have shown that in retinal pigment epithelium (RPE) monolayers, exposure to oxidative stress reduced complement inhibition on the cell surface, with the resulting increase in complement activation leading to vascular endothelial growth factor (VEGF) release and VEGF-receptor-2-mediated disruption of the monolayer barrier function. Complement activation was found to be sublytic and transient and require the assembly of the membrane attack complex (MAC). Here, we asked how this transient, sublytic complement activation could trigger long-term pathological changes in RPE cells. The initial activation of the L-type voltage-gated calcium channels was followed by calcium influx and activation of several kinases. While Erk/Ras activation was found to be transient, Src kinase phosphorylation was sustained. We have shown previously that Src kinase controls VEGF release from RPE cells by altering the activity of the L-type channel. We propose that the prolonged Src kinase activation, and its resulting effects on membrane depolarization and calcium influx, leads to sustained VEGF secretion. In addition, the previously shown effect of the autocrine positive feedback loop in RPE cells, involving VEGF-induced VEGF production and secretion via VEGFR-2 receptors, will augment and prolong the effects of sublytic complement activation. In summary, identification of the links between oxidative stress, chronic, low-grade activation of the complement system, and elevated VEGF expression and secretion might offer opportunities to selectively inhibit pathological VEGF release only.
MeSH term(s)	Calcium Channels, L-Type/physiology ; Cells, Cultured ; Complement Activation/immunology ; Complement System Proteins/immunology ; Complement System Proteins/metabolism ; Enzyme Activation/immunology ; Humans ; Macular Degeneration/immunology ; Macular Degeneration/metabolism ; Macular Degeneration/pathology ; Oxidative Stress/immunology ; Retinal Pigment Epithelium/enzymology ; Retinal Pigment Epithelium/immunology ; Retinal Pigment Epithelium/pathology ; src-Family Kinases/immunology ; src-Family Kinases/metabolism
Chemical Substances	Calcium Channels, L-Type ; Complement System Proteins (9007-36-7) ; src-Family Kinases (EC 2.7.10.2)
Language	English
Publishing date	2014-03-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-1-4614-3209-8_29
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Article ; Online: Smoke exposure causes endoplasmic reticulum stress and lipid accumulation in retinal pigment epithelium through oxidative stress and complement activation.

Kunchithapautham, Kannan / Atkinson, Carl / Rohrer, Bärbel

The Journal of biological chemistry

2014 Volume 289, Issue 21, Page(s) 14534–14546

Abstract: Age-related macular degeneration (AMD) is a complex disease caused by genetic and environmental factors, including genetic variants in complement components and smoking. Smoke exposure leads to oxidative stress, complement activation, endoplasmic ... ...

Abstract	Age-related macular degeneration (AMD) is a complex disease caused by genetic and environmental factors, including genetic variants in complement components and smoking. Smoke exposure leads to oxidative stress, complement activation, endoplasmic reticulum (ER) stress, and lipid dysregulation, which have all been proposed to be associated with AMD pathogenesis. Here we examine the effects of smoke exposure on the retinal pigment epithelium (RPE). Mice were exposed to cigarette smoke or filtered air for 6 months. RPE cells grown as stable monolayers were exposed to 5% cigarette smoke extract (CSE). Effects of smoke were determined by biochemical, molecular, and histological measures. Effects of the alternative pathway (AP) of complement and complement C3a anaphylatoxin receptor signaling were analyzed using knock-out mice or specific inhibitors. ER stress markers were elevated after smoke exposure in RPE of intact mice, which was eliminated in AP-deficient mice. To examine this relationship further, RPE monolayers were exposed to CSE. Short term smoke exposure resulted in production and release of complement C3, the generation of C3a, oxidative stress, complement activation on the cell membrane, and ER stress. Long term exposure to CSE resulted in lipid accumulation, and secretion. All measures were reversed by blocking C3a complement receptor (C3aR), alternative complement pathway signaling, and antioxidant therapy. Taken together, our results provide clear evidence that smoke exposure results in oxidative stress and complement activation via the AP, resulting in ER stress-mediated lipid accumulation, and further suggesting that oxidative stress and complement act synergistically in the pathogenesis of AMD.
MeSH term(s)	Acetylcysteine/pharmacology ; Animals ; Arginine/analogs & derivatives ; Arginine/pharmacology ; Benzhydryl Compounds/pharmacology ; Blotting, Western ; Cells, Cultured ; Complement Activation/drug effects ; Complement Activation/physiology ; Complement Factor B/genetics ; Complement Factor B/metabolism ; Complement Pathway, Alternative/drug effects ; Complement Pathway, Alternative/physiology ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/drug effects ; Endoplasmic Reticulum Stress/physiology ; Free Radical Scavengers/pharmacology ; Heat-Shock Proteins/genetics ; Humans ; Lipid Metabolism ; Lipids/analysis ; Macular Degeneration/genetics ; Macular Degeneration/metabolism ; Macular Degeneration/physiopathology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Nicotine/pharmacology ; Oxidative Stress/drug effects ; Oxidative Stress/physiology ; Receptors, Complement/antagonists & inhibitors ; Receptors, Complement/metabolism ; Retinal Pigment Epithelium/cytology ; Retinal Pigment Epithelium/drug effects ; Retinal Pigment Epithelium/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Smoke ; Nicotiana/chemistry ; Transcription Factor CHOP/genetics
Chemical Substances	Benzhydryl Compounds ; Ddit3 protein, mouse ; Endoplasmic Reticulum Chaperone BiP ; Free Radical Scavengers ; Heat-Shock Proteins ; Lipids ; Receptors, Complement ; SB 290157 ; Smoke ; complement C3a receptor ; Transcription Factor CHOP (147336-12-7) ; Nicotine (6M3C89ZY6R) ; Arginine (94ZLA3W45F) ; Complement Factor B (EC 3.4.21.47) ; Acetylcysteine (WYQ7N0BPYC)
Language	English
Publishing date	2014-04-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M114.564674
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Article: Autophagy is one of the multiple mechanisms active in photoreceptor degeneration.

Kunchithapautham, Kannan / Rohrer, Bärbel

Autophagy

2007 Volume 3, Issue 1, Page(s) 65–66

Abstract: Photoreceptor degeneration in human photoreceptor dystrophies and in the relevant animal models has been thought to be executed by one common mechanism- caspase-mediated apoptosis. However, recent experiments have challenged this concept. Gene defects or ...

Abstract	Photoreceptor degeneration in human photoreceptor dystrophies and in the relevant animal models has been thought to be executed by one common mechanism- caspase-mediated apoptosis. However, recent experiments have challenged this concept. Gene defects or environmental stressors appear to cause oxidative stress and altered metabolism, which appear to induce caspase-dependent and caspase-independent cell death mechanisms such as the activation of cysteine-proteases, lysosomal proteases and autophagy and possibly complement-mediated lysis. In this article, we point out mechanistic parallels between these pathways and summarize our recently published investigation using a temporal analysis of the different pathways, which suggests that the noncaspase-dependent mechanisms may actively participate in the demise of the photoreceptors rather than represent a passive response of the retina to the presence of dying cells. Our investigation revealed that unless the common upstream initiator for a given photoreceptor dystrophy can be found, multiple rescue paradigms need to be used to target all active pathways.
MeSH term(s)	Animals ; Autophagy/physiology ; Mice ; Microtubule-Associated Proteins/metabolism ; Photoreceptor Cells, Vertebrate/metabolism ; Protein Denaturation ; Retinal Degeneration/etiology ; Signal Transduction
Chemical Substances	Map1lc3b protein, mouse ; Microtubule-Associated Proteins
Language	English
Publishing date	2007-01-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review ; Comment
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.4161/auto.3431
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Article: Apoptosis and autophagy in photoreceptors exposed to oxidative stress.

Kunchithapautham, Kannan / Rohrer, Bärbel

Autophagy

2007 Volume 3, Issue 5, Page(s) 433–441

Abstract: Studies on human and animal models of retinal dystrophy have suggested that apoptosis may be the common pathway of photoreceptor cell death. Autophagy, the major cellular degradation process in animal cells, is important in normal development and tissue ... ...

Abstract	Studies on human and animal models of retinal dystrophy have suggested that apoptosis may be the common pathway of photoreceptor cell death. Autophagy, the major cellular degradation process in animal cells, is important in normal development and tissue remodeling, as well as under pathological conditions. Previously we provided evidence that genes, whose products are involved in apoptosis and autophagy, may be coexpressed in photoreceptors undergoing degeneration. Here, we investigated autophagy in oxidative stress-mediated cell death in photoreceptors, analyzing the light-damage mouse model and 661W photoreceptor cells challenged with H(2)O(2). In the in vivo model, we demonstrated a time-dependent increase in the number of TUNEL-positive cells, concomitant with the formation of autophagosomes. In vitro, oxidative stress increased mRNA levels of apoptotic and autophagic marker genes. H(2)O(2) treatment resulted in the accumulation of TUNEL-positive cells, the majority of which contain autophagosomes. To determine whether autophagy and apoptosis might precede each other or co-occur, we performed inhibitor studies. The autophagy inhibitor 3-methyladenine (3-MA), silencing RNA (siRNA) against two genes whose products are required for autophagy (autophagy-related (ATG) gene 5 and beclin 1), as well as the pan-caspase-3 inhibitor, Zvad-fmk, were both found to partially block cell death. Blocking autophagy also significantly decreased caspase-3 activity, whereas blocking apoptosis increased the formation of autophagosomes. The survival effects of 3?MA and zVAD-fmk were not additive; rather treatment with both inhibitors lead to increased cell death by necrosis. In summary, the study first suggests that autophagy participates in photoreceptor cell death possibly by initiating apoptosis. Second, it confirms that cells that normally die by apoptosis will execute cell death by necrosis if the normal pathway is blocked. And third, these results argue that the up-stream regulators of autophagy need to be identified as potential therapeutic targets in photoreceptor degeneration.
MeSH term(s)	Adenine/analogs & derivatives ; Adenine/pharmacology ; Amino Acid Chloromethyl Ketones/pharmacology ; Animals ; Apoptosis/drug effects ; Apoptosis/genetics ; Apoptosis/physiology ; Apoptosis Regulatory Proteins ; Autophagy/drug effects ; Autophagy/genetics ; Autophagy/physiology ; Autophagy-Related Protein 5 ; Base Sequence ; Beclin-1 ; Caspase 3/physiology ; Caspase Inhibitors ; Cysteine Proteinase Inhibitors/pharmacology ; DNA Primers/genetics ; Disease Models, Animal ; Humans ; Hydrogen Peroxide/toxicity ; Light/adverse effects ; Mice ; Mice, Inbred BALB C ; Microtubule-Associated Proteins/antagonists & inhibitors ; Microtubule-Associated Proteins/genetics ; Microtubule-Associated Proteins/physiology ; Necrosis ; Oxidative Stress ; Photoreceptor Cells, Vertebrate/drug effects ; Photoreceptor Cells, Vertebrate/physiology ; Photoreceptor Cells, Vertebrate/radiation effects ; Proteins/antagonists & inhibitors ; Proteins/genetics ; Proteins/physiology ; RNA, Small Interfering/genetics ; Retinal Degeneration/etiology ; Retinal Degeneration/genetics ; Retinal Degeneration/pathology ; Retinal Degeneration/physiopathology
Chemical Substances	Amino Acid Chloromethyl Ketones ; Apoptosis Regulatory Proteins ; Atg5 protein, mouse ; Autophagy-Related Protein 5 ; Beclin-1 ; Becn1 protein, mouse ; Caspase Inhibitors ; Cysteine Proteinase Inhibitors ; DNA Primers ; Microtubule-Associated Proteins ; Proteins ; RNA, Small Interfering ; benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone ; 3-methyladenine (5142-23-4) ; Hydrogen Peroxide (BBX060AN9V) ; Casp3 protein, mouse (EC 3.4.22.-) ; Caspase 3 (EC 3.4.22.-) ; Adenine (JAC85A2161)
Language	English
Publishing date	2007-04-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.4161/auto.4294
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Article ; Online: A comparative analysis of C57BL/6J and 6N substrains; chemokine/cytokine expression and susceptibility to laser-induced choroidal neovascularization.

Schnabolk, Gloriane / Stauffer, Kimberly / O'Quinn, Elizabeth / Coughlin, Beth / Kunchithapautham, Kannan / Rohrer, Bärbel

Experimental eye research

2014 Volume 129, Page(s) 18–23

Abstract: Age-related macular degeneration (AMD) is the most prevalent cause of blindness in the elderly. To study potential underlying mechanisms of AMD, animal models are utilized, focusing mostly on mice. Recently, genomic and phenotypic differences between the ...

Abstract	Age-related macular degeneration (AMD) is the most prevalent cause of blindness in the elderly. To study potential underlying mechanisms of AMD, animal models are utilized, focusing mostly on mice. Recently, genomic and phenotypic differences between the so-called control substrains, C57BL/6J and C57BL/6N, have been described in models of ocular and non-ocular diseases. In particular, the rd8 mutation of the Crb1 gene present in the C57BL/6N has been shown to impact certain ocular phenotypes and appears to augment phenotypes generally associated with inflammation. Here, we investigated angiogenic factor and cytokine expression using pathway arrays as well as the susceptibility to laser-induced choroidal neovascularization (CNV), a model of wet AMD, in the two substrains. Age-matched 3-month-old C57BL/6J and C57BL/6N animals differed in gene expression levels for angiogenic factors and cytokines, with 6N animals expressing higher levels of inflammatory markers than 6Js. Yet laser-induced CNV was comparable in size between the two substrains. This lack of difference in CNV size was correlated with a gene expression profile that was comparable between the two substrains, due to the fact that the degree of change in gene expression of inflammatory markers after CNV was blunted in 6N mice. In summary, significant gene expression differences exist between C57BL/6J and C57BL/6N animals, reinforcing the notion that appropriate litter-mate controls or genetic background controls need to be used. Contrary to our expectation, CNV was not augmented in 6N animals, suggesting that low chronic inflammation in the RPE might provide a level of pre-conditioning and protection against stress.
MeSH term(s)	Animals ; Chemokines/biosynthesis ; Chemokines/genetics ; Choroidal Neovascularization/etiology ; Choroidal Neovascularization/genetics ; Choroidal Neovascularization/metabolism ; Cytokines/biosynthesis ; Cytokines/genetics ; Disease Models, Animal ; Female ; Gene Expression Regulation ; Lasers/adverse effects ; Male ; Mice ; Mice, Inbred C57BL ; Phenotype ; RNA/genetics
Chemical Substances	Chemokines ; Cytokines ; RNA (63231-63-0)
Language	English
Publishing date	2014-10-13
Publishing country	England
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	80122-7
ISSN	1096-0007 ; 0014-4835
ISSN (online)	1096-0007
ISSN	0014-4835
DOI	10.1016/j.exer.2014.10.005
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Article ; Online: Connecting the innate and adaptive immune responses in mouse choroidal neovascularization via the anaphylatoxin C5a and γδT-cells.

Coughlin, Beth / Schnabolk, Gloriane / Joseph, Kusumam / Raikwar, Himanshu / Kunchithapautham, Kannan / Johnson, Krista / Moore, Kristi / Wang, Yi / Rohrer, Bärbel

Scientific reports

2016 Volume 6, Page(s) 23794

Abstract: Neovascular age-related macular degeneration (AMD) is characterized by choroidal neovascularization (CNV). An overactive complement system is associated with AMD pathogenesis, and serum pro-inflammatory cytokines, including IL-17, are elevated in AMD ... ...

Abstract	Neovascular age-related macular degeneration (AMD) is characterized by choroidal neovascularization (CNV). An overactive complement system is associated with AMD pathogenesis, and serum pro-inflammatory cytokines, including IL-17, are elevated in AMD patients. IL-17 is produced by complement C5a-receptor-expressing T-cells. In murine CNV, infiltrating γδT- rather than Th17-cells produce the IL-17 measurable in lesioned eyes. Here we asked whether C5a generated locally in response to CNV recruits IL-17-producing T-cells to the eye. CNV lesions were generated using laser photocoagulation and quantified by imaging; T-lymphocytes were characterized by QRT-PCR. CNV resulted in an increase in splenic IL-17-producing γδT- and Th17-cells; yet in the CNV eye, only elevated levels of γδT-cells were observed. Systemic administration of anti-C5- or anti-C5a-blocking antibodies blunted the CNV-induced production of splenic Th17- and γδT-cells, reduced CNV size and eliminated ocular γδT-cell infiltration. In ARPE-19 cell monolayers, IL-17 triggered a pro-inflammatory state; and splenocyte proliferation was elevated in response to ocular proteins. Thus, we demonstrated that CNV lesions trigger a systemic immune response, augmenting local ocular inflammation via the infiltration of IL-17-producing γδT-cells, which are presumably recruited to the eye in a C5a-dependent manner. Understanding the complexity of complement-mediated pathological mechanisms will aid in the development of an AMD treatment.
MeSH term(s)	Adaptive Immunity ; Animals ; Antibodies, Neutralizing/pharmacology ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/pathology ; Cell Line ; Cell Movement/drug effects ; Choroid/immunology ; Choroid/pathology ; Choroidal Neovascularization/drug therapy ; Choroidal Neovascularization/etiology ; Choroidal Neovascularization/genetics ; Choroidal Neovascularization/immunology ; Complement C5a/antagonists & inhibitors ; Complement C5a/genetics ; Gene Expression ; Humans ; Immunity, Innate ; Injections, Intravenous ; Interleukin-17/genetics ; Interleukin-17/immunology ; Light Coagulation/adverse effects ; Mice ; Mice, Inbred C57BL ; Receptor, Anaphylatoxin C5a/genetics ; Receptor, Anaphylatoxin C5a/immunology ; Receptors, Antigen, T-Cell, gamma-delta/genetics ; Receptors, Antigen, T-Cell, gamma-delta/immunology ; Retinal Pigment Epithelium/cytology ; Retinal Pigment Epithelium/drug effects ; Retinal Pigment Epithelium/immunology ; Spleen/immunology ; Spleen/pathology ; Th17 Cells/immunology ; Th17 Cells/pathology
Chemical Substances	Antibodies, Neutralizing ; Interleukin-17 ; Receptor, Anaphylatoxin C5a ; Receptors, Antigen, T-Cell, gamma-delta ; Complement C5a (80295-54-1)
Language	English
Publishing date	2016-03-31
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/srep23794
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Article ; Online: Differential effects of rapamycin on rods and cones during light-induced stress in albino mice.

Kunchithapautham, Kannan / Coughlin, Beth / Lemasters, John J / Rohrer, Bärbel

Investigative ophthalmology & visual science

2011 Volume 52, Issue 6, Page(s) 2967–2975

Abstract: Purpose: Autophagy is a lysosomal machinery-dependent process that catabolizes cellular components/organelles and proteins in an autophagic vacuole (AV)-dependent and -independent manner, respectively. Short-term exposure of the retina to bright light ... ...

Abstract	Purpose: Autophagy is a lysosomal machinery-dependent process that catabolizes cellular components/organelles and proteins in an autophagic vacuole (AV)-dependent and -independent manner, respectively. Short-term exposure of the retina to bright light results in shortening of the outer segments, concomitant with AV formation. Autophagy is also induced by continuous long-term light damage, leading to photoreceptor cell death. Here the authors examined two questions: is autophagy induced during light damage proapoptotic or antiapoptotic, and are rods and cones affected differently? To this end, Balb/c mice exposed to light damage were treated with rapamycin to increase autophagy. Methods: Balb/c and GFP-LC3 mice were treated with rapamycin/vehicle. Photoreceptor degeneration was induced by 10-day light damage. Autophagy was documented by histologic, biochemical, and molecular tools; rod and cone survival was assessed by histology and electroretinography. Results: Light damage resulted in rod, but not cone, cell loss. Autophagy and AV formation was elicited in response to light damage, which was amplified by rapamycin. Rapamycin treatment significantly improved rod survival and function, reduced apoptosis, and normalized cytokine production that was increased in light damage. However, AV formation in GFP-LC3 mice revealed that light damage or rapamycin treatment induced AVs in cones, concomitant with reduced cone-mediated electroretinograms. Conclusions: Systemic rapamycin treatment provided rod protection; however, AV formation was induced only in cones. Thus, rapamycin may act differentially in stressed photoreceptors; rapamycin might protect rods by normalizing cytokine production, removing damaged proteins by AV-independent autophagy, or both, whereas cones might be protected by AV-dependent autophagy, possibly involving reduced photon capture.
MeSH term(s)	Animals ; Apoptosis/physiology ; Autophagy/physiology ; Blotting, Western ; Caspase 3/metabolism ; Cell Survival/drug effects ; Electroretinography ; Female ; Immunosuppressive Agents/pharmacology ; Injections, Intraperitoneal ; Light/adverse effects ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Radiation Injuries, Experimental/drug therapy ; Radiation Injuries, Experimental/pathology ; Retinal Cone Photoreceptor Cells/drug effects ; Retinal Degeneration/drug therapy ; Retinal Degeneration/pathology ; Retinal Rod Photoreceptor Cells/drug effects ; Reverse Transcriptase Polymerase Chain Reaction ; Sirolimus/pharmacology
Chemical Substances	Immunosuppressive Agents ; Casp3 protein, mouse (EC 3.4.22.-) ; Caspase 3 (EC 3.4.22.-) ; Sirolimus (W36ZG6FT64)
Language	English
Publishing date	2011-05-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	391794-0
ISSN	1552-5783 ; 0146-0404
ISSN (online)	1552-5783
ISSN	0146-0404
DOI	10.1167/iovs.10-6278
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Zs.A 45: Show issues

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Article ; Online: Local production of the alternative pathway component factor B is sufficient to promote laser-induced choroidal neovascularization.

Schnabolk, Gloriane / Coughlin, Beth / Joseph, Kusumam / Kunchithapautham, Kannan / Bandyopadhyay, Mausumi / O'Quinn, Elizabeth C / Nowling, Tamara / Rohrer, Bärbel

Investigative ophthalmology & visual science

2015 Volume 56, Issue 3, Page(s) 1850–1863

Abstract: Purpose: Complement factor B (CFB) is a required component of the alternative pathway (AP) of complement, and CFB polymorphisms are associated with age-related macular degeneration (AMD) risk. Complement factor B is made in the liver, but expression has ...

Abstract	Purpose: Complement factor B (CFB) is a required component of the alternative pathway (AP) of complement, and CFB polymorphisms are associated with age-related macular degeneration (AMD) risk. Complement factor B is made in the liver, but expression has also been detected in retina and retinal pigment epithelium (RPE)-choroid. We investigated whether production of CFB by the RPE can promote AP activation in mouse choroidal neovascularization (CNV). Methods: Transgenic mice expressing CFB under the RPE65 promoter were generated and crossed onto factor B-deficient (CFB-KO) mice. Biological activity was determined in vitro using RPE monolayers and in vivo using laser-induced CNV. Contribution of systemic CFB was investigated using CFB-KO reconstituted with CFB-sufficient serum. Results: Transgenic mice (CFB-tg) expressed CFB in RPE-choroid; no CFB was detected in serum. Cultured CFB-tg RPE monolayers secreted CFB apically and basally upon exposure to oxidative stress that was biologically active. Choroidal neovascularization sizes were comparable between wild-type and CFB-tg mice, but significantly increased when compared to lesions in CFB-KO mice. Injections of CFB-sufficient serum into CFB-KO mice resulted in partial reconstitution of systemic AP activity and significantly increased CNV size. Conclusions: Mouse RPE cells express and secrete CFB sufficient to promote RPE damage and CNV. This further supports that local complement production may regulate disease processes; however, the reconstitution experiments suggest that additional components may be sequestered from the bloodstream. Understanding the process of ocular complement production and regulation will further our understanding of the AMD disease process and the requirements of a complement-based therapeutic.
MeSH term(s)	Animals ; Blotting, Western ; Cells, Cultured ; Choroid/pathology ; Choroidal Neovascularization/etiology ; Choroidal Neovascularization/genetics ; Choroidal Neovascularization/metabolism ; Complement Factor B/biosynthesis ; Complement Factor B/genetics ; Complement Pathway, Alternative/genetics ; Disease Models, Animal ; Electroretinography ; Enzyme-Linked Immunosorbent Assay ; Gene Expression Regulation ; Lasers/adverse effects ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; RNA, Messenger/genetics ; Real-Time Polymerase Chain Reaction ; Retinal Pigment Epithelium/pathology ; Retinal Pigment Epithelium/physiopathology ; Tomography, Optical Coherence
Chemical Substances	RNA, Messenger ; Complement Factor B (EC 3.4.21.47)
Language	English
Publishing date	2015-01-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	391794-0
ISSN	1552-5783 ; 0146-0404
ISSN (online)	1552-5783
ISSN	0146-0404
DOI	10.1167/iovs.14-15910
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Article: Paradoxical role of BDNF: BDNF+/- retinas are protected against light damage-mediated stress.

Wilson, R Brooks / Kunchithapautham, Kannan / Rohrer, Bärbel

Investigative ophthalmology & visual science

2007 Volume 48, Issue 6, Page(s) 2877–2886

Abstract: Purpose: Photoreceptors can be prevented from undergoing apoptosis in response to constant light by the application of exogenous neuroprotective agents, including brain-derived neurotrophic factor (BDNF). BDNF, however, cannot exert its effect directly ... ...

Abstract	Purpose: Photoreceptors can be prevented from undergoing apoptosis in response to constant light by the application of exogenous neuroprotective agents, including brain-derived neurotrophic factor (BDNF). BDNF, however, cannot exert its effect directly on photoreceptors because they do not express receptors for BDNF. It has been proposed that BDNF released from Müller cells provides a feed-forward loop, increasing ciliary neurotrophic factor (CNTF) and basic fibroblast growth factor (bFGF) production in Müller cells, which may enhance photoreceptor survival. The authors hypothesized that retinas with reduced BDNF levels in which the BDNF-mediated release of neuroprotective signals is dampened are more susceptible to light-induced photoreceptor degeneration. Methods: Young adult BDNF+/+ and BDNF+/- littermates (B6.129-BDNF(tm1-LT)) were analyzed. Retinal neurotrophin and growth factor mRNA levels were determined by quantitative RT-PCR, photoreceptor function was assessed through electroretinography, and survival was documented in morphologic sections and in TUNEL assays. Oxidative stress was assayed by measuring glutathione peroxidase activity. Results: At baseline, BDNF+/- animals had significantly increased levels of glial-derived neurotrophic factor (GDNF) mRNA compared with their wild-type littermates. After light damage GDNF, CNTF, and BDNF mRNA levels dropped 14- to 16-fold in the BDNF+/+ mice but remained almost unchanged compared with baseline levels in the BDNF+/- mice. Preservation of neurotrophin levels in BDNF+/- mice correlated with photoreceptor cell survival, preservation of function, and reduced oxidative stress. Conclusions: Contrary to the hypothesis, reducing BDNF levels resulted in photoreceptor protection against light damage. Survival was paralleled by a reduction in oxidative stress and the preservation of neurotrophin levels, suggesting that chronic reduction of BDNF in the retina provides a level of preconditioning against stress.
MeSH term(s)	Animals ; Brain-Derived Neurotrophic Factor/physiology ; Cell Survival ; Ciliary Neurotrophic Factor/genetics ; Electroretinography ; Female ; Glial Cell Line-Derived Neurotrophic Factor/genetics ; Glutathione Peroxidase/metabolism ; In Situ Nick-End Labeling ; Light/adverse effects ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Nerve Growth Factors/genetics ; Oxidative Stress ; RNA, Messenger/metabolism ; Radiation Injuries, Experimental/metabolism ; Radiation Injuries, Experimental/pathology ; Radiation Injuries, Experimental/prevention & control ; Retina/radiation effects ; Retinal Degeneration/metabolism ; Retinal Degeneration/pathology ; Retinal Degeneration/prevention & control ; Reverse Transcriptase Polymerase Chain Reaction
Chemical Substances	Brain-Derived Neurotrophic Factor ; Ciliary Neurotrophic Factor ; Glial Cell Line-Derived Neurotrophic Factor ; Nerve Growth Factors ; RNA, Messenger ; Glutathione Peroxidase (EC 1.11.1.9)
Language	English
Publishing date	2007-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	391794-0
ISSN	1552-5783 ; 0146-0404
ISSN (online)	1552-5783
ISSN	0146-0404
DOI	10.1167/iovs.06-1079
Database	MEDical Literature Analysis and Retrieval System OnLINE

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