187 research outputs found
Novel molecular mechanisms of neuronal and vascular protection in experimental glaucoma
Le glaucome est la deuxiÚme cause de cécité irréversible dans le monde. La perte
de vision qui se produit lors du glaucome sâexplique par une dĂ©gĂ©nĂ©rescence du nerf
optique et une mort progressive et sélective des cellules ganglionnaires de la rétine
(CRG). L'hypertension oculaire est un facteur de risque majeur dans le glaucome, mais
des défauts du champ visuel continuent à se développer chez un contingent de patients
malgré l'administration de médicaments qui abaissent la pression intraoculaire (PIO). Par
conséquent, bien que la PIO représente le seul facteur de risque modifiable dans le
développement du glaucome, son contrÎle ne suffit pas à protéger les CRGs et préserver
la fonction visuelle chez de nombreux patients. Dans ce contexte, j'ai avancé l'hypothÚse
centrale voulant que les stratégies de traitement du glaucome visant à promouvoir la
protection structurale et fonctionnelle des CRGs doivent agir sur les mécanismes
moléculaires qui conduisent à la mort des ces neurones.
Dans la premiÚre partie de ma thÚse, j'ai caractérisé l'effet neuroprotecteur de la
galantamine, un inhibiteur de l'acétylcholinestérase qui est utilisé cliniquement dans le
traitement de la maladie d'Alzheimer. Cette Ă©tude sâest basĂ©e sur l'hypothĂšse que la
galantamine, en modulant l'activité du récepteur de l'acétylcholine, puisse améliorer la
survie des CRGs lors du glaucome. Nous avons utilisé un modÚle expérimental bien
caractĂ©risĂ© d'hypertension oculaire induite par lâadministration d'une solution saline
hypertonique dans une veine épisclérale de rats Brown Norway. Les résultats de cette
étude (Almasieh et al. Cell Death and Disease, 2010) ont démontré que l'administration
quotidienne de galantamine améliore de maniÚre significative la survie des corps
cellulaires et des axones CRGs. La protection structurelle des CRGs sâaccompagne dâune
préservation remarquable de la fonction visuelle, évaluée par l'enregistrement des
potentiels évoqués visuels (PEV) dans le collicule supérieur, la cible principale des CRGs
chez le rongeur. Une autre constatation intéressante de cette étude est la perte
substantielle de capillaires rétiniens et la réduction du débit sanguin associé à la perte des
CRGs dans le glaucome expérimental. Il est trÚs intéressant que la galantamine ait
également favorisé la protection de la microvascularisation et amélioré le débit sanguin
rétinien des animaux glaucomateux (Almasieh et al. en préparation). J'ai notamment
démontré que les neuro-et vasoprotections médiées par la galantamine se produisent par
iv
l'activation des récepteurs muscariniques de l'acétylcholine.
Dans la deuxiÚme partie de ma thÚse, j'ai étudié le rÎle du stress oxydatif ainsi que
l'utilisation de composés réducteurs pour tester l'hypothÚse que le blocage d'une
augmentation de superoxyde puisse retarder la mort des CRG lors du glaucome
expérimental. J'ai profité d'un composé novateur, un antioxydant à base de phosphineborane
(PB1), pour tester sur son effet neuroprotecteur et examiner son mécanisme
d'action dans le glaucome expérimental. Les données démontrent que l'administration
intraoculaire de PB1 entraĂźne une protection significative des corps cellulaire et axones
des CRGs. Les voies moléculaires conduisant à la survie neuronale médiée par PB1 ont
été explorées en déterminant la cascade de signalisation apoptotique en cause. Les
rĂ©sultats dĂ©montrent que la survie des CRGs mĂ©diĂ©e par PB1 ne dĂ©pend pas dâune
inhibition de signalisation de protéines kinases activées par le stress, y compris ASK1,
JNK ou p38. Par contre, PB1 induit une augmentation marquée des niveaux rétiniens de
BDNF et une activation en aval de la voie de survie des ERK1 / 2 (Almasieh et al.
Journal of Neurochemistry, 2011).
En conclusion, les résultats présentés dans cette thÚse contribuent à une meilleure
compréhension des mécanismes pathologiques qui conduisent à la perte de CRGs dans le
glaucome et pourraient fournir des pistes pour la conception de nouvelles stratégies
neuroprotectrices et vasoprotectrices pour le traitement et la gestion de cette maladie.Glaucoma is the second cause of irreversible blindness worldwide. Loss of vision
in glaucoma is accompanied by progressive optic nerve degeneration and selective loss of
retinal ganglion cells (RGCs). Ocular hypertension is a major risk factor in glaucoma, but
visual field defects continue to progress in a large group of patients despite the use of
drugs that lower intraocular pressure (IOP). Therefore, although IOP is the sole
modifiable risk factor in the development of glaucoma, its regulation is not sufficient to
protect RGCs and preserve visual function in many affected patients. To address this
issue, I put forward the central hypothesis that effective therapeutic strategies for
glaucoma must interfere with molecular mechanisms that lead to RGC death to
successfully promote structural and functional protection of these neurons.
In the first part of my thesis, I characterized the neuroprotective effect of
galantamine, an acetylcholinesterase inhibitor that is clinically used for the treatment of
Alzheimerâs disease. The specific hypothesis of this study was that galantamine, by
modulating acetylcholine receptor activity, can improve the survival of injured RGCs in
glaucoma. A well characterized experimental model of ocular hypertension induced by
administration of a hypertonic saline into an episcleral vein of Brown Norway rats was
used. The results of this study (Almasieh et al. Cell Death and Disease, 2010)
demonstrated that daily administration of galantamine significantly improved the survival
of RGC soma and axons in this model. Structural protection of RGCs correlated with
substantial preservation of visual function, assessed by recording visual evoked potentials
(VEPs) from the superior colliculus, the primary target of RGCs in the rodent brain. An
interesting finding during the course of my thesis was that there is a substantial loss of
retinal capillaries and a reduction in retinal blood that correlates with RGC loss in
experimental glaucoma. Interestingly, galantamine also promoted the protection of the
microvasculature and improved retinal blood flow in ocular hypertensive animals
(Almasieh et al. in preparation). Importantly, I demonstrated that galantamine-mediated
neuro- and vasoprotection occur through activation of muscarinic acetylcholine receptors.
In the second part of my thesis, I investigated the role of oxidative stress and the
use of reducing compounds to test the hypothesis that blockade of a superoxide burst may
delay RGC death in experimental glaucoma. I took advantage of a novel phosphinevi
borane based antioxidant compound available to us (PB1) to investigate its
neuroprotective effect and mechanism of action in experimental glaucoma. The data
demonstrate that intraocular administration of PB1 resulted in significant protection of
RGC soma and axons. I also explored the molecular pathways leading to PB1-mediated
neuronal survival by analyzing the components of survival and apoptotic signaling
pathways involved in this response. My results show that PB1-mediated RGC survival
did not correlate with inhibition of stress-activated protein kinase signaling, including
ASK1, JNK or p38. Instead, PB1 led to a striking increase in retinal BDNF levels and
downstream activation of the pro-survival ERK1/2 pathway (Almasieh et al. Journal of
Neurochemistry, 2011).
In conclusion, the findings presented in this thesis contribute to a better
understanding of the pathological mechanisms underlying RGC loss in glaucoma and
might provide insights into the design of novel neuroprotective and vasoprotective
strategies for the treatment and management of this disease
Assessment of Mercury Accumulation and Magnification in a Freshwater Food Chain: Sediment, Benthos and Benthivorous Fish
Background: Present study was conducted to measure the level of total mercury (tHg) in sediments, benthos and benthivorous fish (i.e., common carp) for determining Biota (Benthos)-Sediment Accumulation Factor (BSAF), as well as Biomagnification Factor (BMF) of tHg between two trophic levels of benthos and benthivorous fish caught from Sanandaj Gheshlagh Reservoir (SGR) in the west of Iran.
Methods: Samples of sediments and benthos biomasses were collected from three sampling stations. Common carps were captured around the selected stations during July to December 2010.
Results: Means accumulated tHg (±SE) in sediments, benthos masses and muscle tissue of common carp were 117.66±9.72, 94.3±5.02 and 233.21±20.67 ng g-1 dry weight, respectively. Means accumulated tHg in benthos masses and muscle tissue of the common carp during the studying months showed no significant differences (P>0.05), while it was significantly differed in sediment samples (P<0.05). Results showed that there were statistically significant differences between accumulated tHg between sediment and benthos mass samples collected from the study sites (P<0.05).
Conclusion: During the study, all calculated BSAF measurements were less than one, indicating transmission of mercury from sediment to benthos was not considerable. However, mercury BMFs was higher than one, denoting mercury biomagnification occurred from the benthos trophic level to the higher trophic level (i.e., common carp) in study site. Hence, the health considerations have to be taken in to the account for consumption of fishery products of SGR
VEGF-A165b is an endogenous neuroprotective splice isoform of vascular endothelial growth factor A in vivo and in vitro
Vascular endothelial growth factor (VEGF) A is generated as two isoform families by alternative RNA splicing, represented by VEGF-A165a and VEGF-A165b. These isoforms have opposing actions on vascular permeability, angiogenesis, and vasodilatation. The proangiogenic VEGF-A165a isoform is neuroprotective in hippocampal, dorsal root ganglia, and retinal neurons, but its propermeability, vasodilatatory, and angiogenic properties limit its therapeutic usefulness. In contrast, a neuroprotective effect of endogenous VEGF-A165b on neurons would be advantageous for neurodegenerative pathologies. Endogenous expression of human and rat VEGF-A165b was detected in hippocampal and cortical neurons. VEGF-A165b formed a significant proportion of total VEGF-A in rat brain. Recombinant human VEGF-A165b exerted neuroprotective effects in response to multiple insults, including glutamatergic excitotoxicity in hippocampal neurons, chemotherapy-induced cytotoxicity of dorsal root ganglion neurons, and retinal ganglion cells (RGCs) in rat retinal ischemia-reperfusion injury in vivo. Neuroprotection was dependent on VEGFR2 and MEK1/2 activation but not on p38 or phosphatidylinositol 3-kinase activation. Recombinant human VEGF-A165b is a neuroprotective agent that effectively protects both peripheral and central neurons in vivo and in vitro through VEGFR2, MEK1/2, and inhibition of caspase-3 induction. VEGF-A165b may be therapeutically useful for pathologies that involve neuronal damage, including hippocampal neurodegeneration, glaucoma diabetic retinopathy, and peripheral neuropathy. The endogenous nature of VEGF-A165b expression suggests that non-isoform-specific inhibition of VEGF-A (for antiangiogenic reasons) may be damaging to retinal and sensory neurons
Thiol redox homeostasis in neurodegenerative disease
This review provides an overview of the biochemistry of thiol redox couples and the significance of thiol redox homeostasis in neurodegenerative disease. The discussion is centred on cysteine/cystine redox balance, the significance of the xc- cystine-glutamate exchanger and the association between protein thiol redox balance and neurodegeneration, with particular reference to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and glaucoma. The role of thiol disulphide oxidoreductases in providing neuroprotection is also discussed
Advances in exosome therapies in ophthalmologyâFrom bench to clinical trial
During the last decade, the fields of advanced and personalized therapeutics have been constantly evolving, utilizing novel techniques such as gene editing and RNA therapeutic approaches. However, the method of delivery and tissue specificity remain the main hurdles of these approaches. Exosomes are natural carriers of functional small RNAs and proteins, representing an area of increasing interest in the field of drug delivery. It has been demonstrated that the exosome cargo, especially miRNAs, is at least partially responsible for the therapeutic effects of exosomes. Exosomes deliver their luminal content to the recipient cells and can be used as vesicles for the therapeutic delivery of RNAs and proteins. Synthetic therapeutic drugs can also be encapsulated into exosomes as they have a hydrophilic core, which makes them suitable to carry water-soluble drugs. In addition, engineered exosomes can display a variety of surface molecules, such as peptides, to target specific cells in tissues. The exosome properties present an added advantage to the targeted delivery of therapeutics, leading to increased efficacy and minimizing the adverse side effects. Furthermore, exosomes are natural nanoparticles found in all cell types and as a result, they do not elicit an immune response when administered. Exosomes have also demonstrated decreased long-term accumulation in tissues and organs and thus carry a low risk of systemic toxicity. This review aims to discuss all the advances in exosome therapies in ophthalmology and to give insight into the challenges that would need to be overcome before exosome therapies can be translated into clinical practice
Sphingolipids as critical players in retinal physiology and pathology
Sphingolipids have emerged as bioactive lipids involved in the regulation of many physiological and pathological processes. In the retina, they have been established toparticipate in numerousprocesses, suchas neuronal survival and death, proliferation and migration of neuronal and vascular cells, inflammation, and neovascularization. Dysregulation of sphingolipids is therefore crucial in the onset and progression of retinal diseases. This review examines the involvement of sphingolipids in retinal physiology and diseases. Ceramide (Cer) has emerged as a common mediator of inflammation and death of neuronal and retinal pigment epithelium cells in animal models of retinopathies such as glaucoma, age-related macular degeneration (AMD), and retinitis pigmentosa. Sphingosine- 1-phosphate (S1P) has opposite roles, preventing photoreceptor and ganglion cell degeneration but also promoting inflammation, fibrosis, and neovascularization in AMD, glaucoma, and pro-fibrotic disorders. Alterations in Cer, S1P, and ceramide 1- phosphate may also contribute to uveitis. Notably, use of inhibitors that either prevent Cer increase or modulate S1P signaling, such as Myriocin, desipramine, and Fingolimod (FTY720), preserves neuronal viability and retinal function. These findings underscore the relevance of alterations in the sphingolipid metabolic network in the etiology of multiple retinopathies and highlight the potential of modulating their metabolism for the design of novel therapeutic approaches.Fil: Simon, Maria Victoria. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - BahĂa Blanca. Instituto de Investigaciones BioquĂmicas de BahĂa Blanca. Universidad Nacional del Sur. Instituto de Investigaciones BioquĂmicas de BahĂa Blanca; Argentina. Universidad Nacional del Sur. Departamento de BiologĂa, BioquĂmica y Farmacia; ArgentinaFil: Basu, Sandip K.. University of Tennessee; Estados UnidosFil: Qaladize, Bano. University of Tennessee; Estados UnidosFil: Grambergs, Richards. University of Tennessee; Estados UnidosFil: Rotstein, Nora Patricia. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - BahĂa Blanca. Instituto de Investigaciones BioquĂmicas de BahĂa Blanca. Universidad Nacional del Sur. Instituto de Investigaciones BioquĂmicas de BahĂa Blanca; Argentina. Universidad Nacional del Sur. Departamento de BiologĂa, BioquĂmica y Farmacia; ArgentinaFil: Mandal, Nawajes .A.. University of Tennessee; Estados Unido
Analysis of apoptosis methods recently used in Cancer Research and Cell Death & Disease publications
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