Collagen-Based Scaffolds for Cell Therapies in the Injured Brain

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Animal Models of Diabetic Retinopathy: Summary and Comparison

Diabetic retinopathy (DR) is a microvascular complication associated with chronic exposure to hyperglycemia and is a major cause of blindness worldwide. Although clinical assessment and retinal autopsy of diabetic patients provide information on the features and progression of DR, its underlying pathophysiological mechanism cannot be deduced. In order to have a better understanding of the development of DR at the molecular and cellular levels, a variety of animal models have been developed. They include pharmacological induction of hyperglycemia and spontaneous diabetic rodents as well as models of angiogenesis without diabetes (to compensate for the absence of proliferative DR symptoms). In this review, we summarize the existing protocols to induce diabetes using STZ. We also describe and compare the pathological presentations, in both morphological and functional aspects, of the currently available DR animal models. The advantages and disadvantages of using different animals, ranging from zebrafish, rodents to other higher-order mammals, are also discussed. Until now, there is no single model that displays all the clinical features of DR as seen in human. Yet, with the understanding of the pathological findings in these animal models, researchers can select the most suitable models for mechanistic studies or drug screening.published_or_final_versio

Carriers in Cell-Based Therapies for Neurological Disorders

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Stem Cell Therapy for Retinopathy of Prematurity

Retinopathy of Prematurity (ROP) is a leading cause of childhood blindness that severely affecting the quality of life of these children. Few treatment options are available but without favorable outcomes. Stem cell therapy, through its proven potential in tissue regeneration, provides an attractive therapeutic approach in treating ROP and thereby restoring vision.published_or_final_versio

Sustained Delivery of Bioactive GDNF from Collagen and Alginate-Based Cell-Encapsulating Gel Promoted Photoreceptor Survival in an Inherited Retinal Degeneration Model

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Lutein enhances survival and reduces neuronal damage in cerebral and retinal ischemia/reperfusion injury

Poster session 3: NeuroprotectionConference theme: Translational Neuroscience: From Molecules To ManPurpose Stroke is one of the leading causes of death worldwide. Protective agents that could diminish the injuries induced by cerebral ischemia/reperfusion (I/R) are crucial to alleviate the detrimental outcome of stroke. Retinal I/R also occurs in many ocular diseases and leads to neuronal death and therefore blindness. Lutein, a safe and potent antioxidant, is known to protect the retina in age-related macular degeneration. The aim of this study is to investigate the protective roles of lutein in cerebral and retinal I/R injury. Methods Two-hour cerebral ischemia was induced by unilateral middle cerebral artery occlusion (MCAo) in mice. Either lutein (0.2mg/kg) or vehicle was given to mice intraperitoneally 1hr after MCAo and 1hr after reperfusion. Neurological deficits were evaluated at 22hr after reperfusion while survival rate was assessed daily until 7 days after reperfusion. Flash electroretinogram (flash ERG) was taken to assess retinal function. After sacrifice, mouse brains were cut into 2mm-thick coronal slices and stained with 2% 2,3,5-triphenyltetrazolium chloride to determine the infarct size after MCAo. Eyes were also enucleated. Paraffin-embedded brain and retinal sections were prepared for TUNEL assay and immunohistochemistry. Protein lysate was collected for Western blotting experiments. Lutein's effect on Müller cells was further evaluated using a model of cobalt chloride-induced hypoxia in immortalized rat Müller cells (rMC-1). Results Higher survival rate, better neurological scores, smaller infarct area and smaller infarct volume were noted in the lutein-treated group. Immunohistochemistry data showed a decrease of immunoreactivity of nitrotyrosine, poly(ADP-ribose) and NFkB in the lutein-treated brains. Western blotting data showed decreased levels of Cox-2, pERK, and pIkB, but increased levels of Bcl-2, heat shock protein 70 and pAkt in the lutein-treated brains. In the retina, severe cell loss in retinal ganglion cell (RGC) layer was noted after I/R injury. Increased oxidative stress was observed in the injured retina. Lutein treatment protected RGC as well as decreased oxidative stress in I/R retina. Lutein treatment also minimized the deterioration of b-wave/a-wave ratio and oscillatory potentials in flash ERG as well as inhibited the up-regulation of GFAP in retinal I/R injury. In the cultured Müller cells, lutein treatment reduced level of nuclear NF-kB together with decreased levels of IL-1b and Cox- 2. Conclusions Post-treatment of lutein protected both the brain and retina from I/R injury. The neuroprotective effect of lutein was associated with reduced oxidative stress. Less production of pro-inflammatory factors from Müller cells suggested an anti-inflammatory role of lutein in retinal ischemic/hypoxic injury. Our results suggest that lutein could diminish the deleterious outcomes of cerebral and retinal I/R probably by its antiapoptotic, anti-oxidative and anti-inflammatory properties. Lutein may have a therapeutic role in protecting the brain in stroke and inner retina in eye diseases with acute ischemia.published_or_final_versio

Impact of split completeness on future liver remnant hypertrophy in associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) in hepatocellular carcinoma: Complete-ALPPS versus partial-ALPPS

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Outcomes of right-lobe and left-lobe living-donor liver transplantations using small-for-size grafts

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Neuroprotective effects of lutein in a rat model of retinal detachment

Background: Retinal detachment (RD) is a leading cause of blindness, and although final surgical re-attachment rate has greatly improved, visual outcome in many macula-off detachments is disappointing, mainly because of photoreceptor cell death. We previously showed that lutein is anti-apoptotic in rodent models of ischemia/reperfusion injury. The objective of this study is to investigate lutein as a possible pharmacological adjunct to surgery. Methods: Subretinal injections of 1.4 % sodium hyaluronate were used to induce RD in Sprague-Dawley rats until their retinae were approximately 70 % detached. Daily injections of corn oil (control group) or 0.5 mg/kg lutein in corn oil (treatment group) were given intraperitoneally starting 4 h after RD induction. Animals were euthanized 3 days and 30 days after RD and their retinae were analyzed for photoreceptor apoptosis and cell survival at the outer nuclear layer (ONL) using TUNEL staining and cell counting on retinal sections. Glial fibrillary acidic protein (GFAP) and rhodopsin (RHO) expression were evaluated with immunohistochemistry. Western blotting was done with antibodies against cleaved caspase-3, cleaved caspase-8 and cleaved caspase-9 to delineate lutein's mechanism of action in the apoptotic cascade. To seek a possible therapeutic time window, the same set of experiments was repeated with treatment commencing 36 h after RD. Results: When lutein was given 4 h after RD, there were significantly fewer TUNEL-positive cells in ONL 3 days after RD when compared with the vehicle group. Cell counting showed that there were significantly more nuclei in ONL in lutein-treated retinae by day 30. Treatment groups also showed significantly reduced GFAP immunoreactivity and preserved RHO expression. At day 3 after RD, Western blotting showed reduced expression of cleaved caspase-3 and cleaved caspase-8 in the treatment group. No difference was found for cleaved caspase-9. When lutein was given 36 h after RD similar results were observed. Conclusions: Our results suggest that lutein is a potent neuroprotective agent that can salvage photoreceptors in rats with RD, with a therapeutic window of at least 36 h. The use of lutein in patients with RD may serve as an adjunct to surgery to improve visual outcomes. © 2012 The Author(s).published_or_final_versio

Aldose reductase deficiency protects the retinal neurons in a mouse model of retinopathy of prematurity

Poster Presentation: P64PURPOSE: Retinopathy of prematurity (ROP) is a common retinal disease occurred in premature babies. It is found to be related to oxidative stress while dysfunction of the neural retina has also been documented. We previously showed that genetic deletion or pharmacological inhibition of aldose reductase (AR), a rate- limiting enzyme in the polyol pathway, prevented ischemia-induced retinal ganglion cell (RGC) loss and oxidative stress. Here, we assessed the effects of AR deletion on retinal neurons using a mouse model of ROP. METHODS: Seven-day-old mouse pups were exposed to 75% oxygen for five days and returned to room air. The pathological neuronal changes were examined and compared between wild-type (WT) and AR-deficient retinae on P14 and P17 (P, postnatal). Retinal thickness was measured and immunohistochemistry for calbindin, calretinin, PKCα, Tuj1, glial fibrillary acidic protein (GFAP), nitrotyrosine (NT), as well as poly(ADP-ribose) (PAR) was performed. RESULTS: After hyperoxia exposure, significantly reduced inner nuclear layer (INL) and inner plexiform layer (IPL) thickness were found in both genotypes. The intensity of calbindin staining for horizontal cells in INL was reduced in the WT retinae but not in AR-deficient retinae. In addition, significant reduction was found in calretinin-positive amacrine cell bodies in central INL especially in WT retinae. Serious distortion was also observed in the three calretinin-positive strata along IPL in the WT retinae but not AR-deficient retinae on P17. Moreover, increased GFAP intensity across IPL indicating Müller cell processes was observed in AR-deficient retinae on P14 and in WT retinae on P17. Furthermore, increased NT immunoreactivity in INL and nuclear or para-nuclear PAR staining along GCL were observed in WT retina while these changes were not apparent in AR-deficient retina. CONCLUSION: Our observations demonstrated morphological changes of retinal neurons in the mouse model of ROP and indicated that AR deficiency showed neuronal protection in the retina, possibly through modulating glial responses and reducing oxidative stress.postprin