Inhibition Of Cell Death Pathways Research Articles

Class IIa HDACs inhibit cell death pathways and protect muscle integrity in response to lipotoxicity

Lipotoxicity, the accumulation of lipids in non-adipose tissues, alters the metabolic transcriptome and mitochondrial metabolism in skeletal muscle. The mechanisms involved remain poorly understood. Here we show that lipotoxicity increased histone deacetylase 4 (HDAC4) and histone deacetylase 5 (HDAC5), which reduced the expression of metabolic genes and oxidative metabolism in skeletal muscle, resulting in increased non-oxidative glucose metabolism. This metabolic reprogramming was also associated with impaired apoptosis and ferroptosis responses, and preserved muscle cell viability in response to lipotoxicity. Mechanistically, increased HDAC4 and 5 decreased acetylation of p53 at K120, a modification required for transcriptional activation of apoptosis. Redox drivers of ferroptosis derived from oxidative metabolism were also reduced. The relevance of this pathway was demonstrated by overexpression of loss-of-function HDAC4 and HDAC5 mutants in skeletal muscle of obese db/db mice, which enhanced oxidative metabolic capacity, increased apoptosis and ferroptosis and reduced muscle mass. This study identifies HDAC4 and HDAC5 as repressors of skeletal muscle oxidative metabolism, which is linked to inhibition of cell death pathways and preservation of muscle integrity in response to lipotoxicity.

A Review on Polyphenols in Salicornia ramosissima with Special Emphasis on Their Beneficial Effects on Brain Ischemia.

There has been an increasing interest in the consumption of halophytes as a healthy food in the last few years. Salicornia ramosissima is a seasonal Mediterranean halophyte with an interesting profile of bioactive compounds, including more than 60 identified polyphenols with a broad range of biological activities. Accumulating evidence supports the role of dietary polyphenols in the prevention of cardiovascular diseases, such as stroke. Stroke is the second cause of death worldwide and it is estimated that a substantial proportion of stroke incidence and recurrence may be prevented by healthier dietary patterns. Here, we have grouped the phenolic acids and flavonoids identified in S. ramosissima and reviewed their potential protective effect on brain ischemia, which are mostly related to the reduction of oxidative stress and inflammation, the inhibition of cell death pathways and their role in the preservation of the vascular function. Despite the fact that most of these compounds have been reported to be neuroprotective through multiple mechanisms, human studies are still scarce. Given the safe profile of polyphenols identified in S. ramosissima, this halophyte plant could be considered as a source of bioactive compounds for the nutraceutical industry.

Early onset senescence and cognitive impairment in a murine model of repeated mTBI

Mild traumatic brain injury (mTBI) results in broad neurological symptoms and an increased risk of being diagnosed with a neurodegenerative disease later in life. While the immediate oxidative stress response and post-mortem pathology of the injured brain has been well studied, it remains unclear how early pathogenic changes may drive persistent symptoms and confer susceptibility to neurodegeneration. In this study we have used a mouse model of repeated mTBI (rmTBI) to identify early gene expression changes at 24 h or 7 days post-injury (7 dpi). At 24 h post-injury, gene expression of rmTBI mice shows activation of the DNA damage response (DDR) towards double strand DNA breaks, altered calcium and cell–cell signalling, and inhibition of cell death pathways. By 7 dpi, rmTBI mice had a gene expression signature consistent with induction of cellular senescence, activation of neurodegenerative processes, and inhibition of the DDR. At both timepoints gliosis, microgliosis, and axonal damage were evident in the absence of any gross lesion, and by 7 dpi rmTBI also mice had elevated levels of IL1β, p21, 53BP1, DNA2, and p53, supportive of DNA damage-induced cellular senescence. These gene expression changes reflect establishment of processes usually linked to brain aging and suggests that cellular senescence occurs early and most likely prior to the accumulation of toxic proteins. These molecular changes were accompanied by spatial learning and memory deficits in the Morris water maze. To conclude, we have identified DNA damage-induced cellular senescence as a repercussion of repeated mild traumatic brain injury which correlates with cognitive impairment. Pathways involved in senescence may represent viable treatment targets of post-concussive syndrome. Senescence has been proposed to promote neurodegeneration and appears as an effective target to prevent long-term complications of mTBI, such as chronic traumatic encephalopathy and other related neurodegenerative pathologies.

Modulation of proteomic and inflammatory signals by Bradykinin in podocytes

Podocyte damage is one of the hallmarks of diabetic nephropathy leading to proteinuria and kidney damage. The underlying mechanisms of podocyte injury are not well defined. Bradykinin (BK) was shown to contribute to diabetic kidney disease. Here, we evaluated the temporal changes in proteome profile and inflammatory signals of podocytes in response to BK (10−7M). Protein profile was evaluated by liquid chromatography mass Spectrometry (LC-MS/MS) analysis. Proteome profile analysis of podocytes treated with BK (10−7M) for 3 and 6 h, revealed 61 proteins that were differentially altered compared to unstimulated control podocytes. Pathway enrichment analysis suggested inhibition of cell death pathways, engagement of cytoskeletal elements and activation of inflammatory pathways. One of the inflammatory proteins that was identified to be induced by BK treatment is Prostaglandin (PG) H Synthase-2 (Cyclooxygenase-2, COX-2). In addition, BK significantly induced the production and release of PGE2 and this effect was inhibited by both COX-2 and MEK Kinase inhibitors, demonstrating that the production of PGE2 by BK is mediated via COX-2 and MAPK-dependent mechanisms. These findings provide a global understanding of the effector modulated proteome in response to BK and also reveal BK as an important modulator of inflammation and a potential player in podocyte injury.

Beneficial consequences of Lupeol on middle cerebral artery-induced cerebral ischemia in the rat involves Nrf2 and P38 MAPK modulation.

Lupeol has been reported to exhibit anti-inflammatory and anti-tumor activities in many diseases, but its potential effects in cerebral ischemia injury have not been studied to date. In this work we present evidence for a beneficial effect of lupeol in a rat model of middle cerebral artery occlusion (MCAO) followed by reperfusion (MCAO/R) injury and provide some histological and biochemical evidence for its mechanism of action. A cerebral MCAO rat model was established by vascular occlusion for 2h, followed by 24h reperfusion period. The infarct volume, neurological deficits, and brain water content were compared with animals treated during reperfusion with different concentrations of lupeol. Macroscopic parameters, cell viability, pro-inflammatory factors generation, as well as oxidative stress parameters and associated apoptotic signaling cascades were evaluated. Treatment with lupeol significantly reduced the cerebral infarct volume and water content and recovered neuro behavioral functions in affected rats. Lupeol treatment down-regulated the expression of oxidative stress and inflammation factors. In addition, lupeol activated Nrf2, suppressed caspase-3 activity, reduced BAX/Bcl-2 ratio and inhibited phosphorylation of p38 MAPK. The data suggest that lupeol may exert protective effects against cerebral ischemia by suppressing oxidative stress and reduction of inflammation factors possible via activation of nuclear transcription factors and inhibition of cell death pathways.

Collaboration of MYC and RUNX2 in lymphoma simulates T-cell receptor signaling and attenuates p53 pathway activity.

MYC and RUNX oncogenes each trigger p53‐mediated failsafe responses when overexpressed in vitro and collaborate with p53 deficiency in vivo. However, together they drive rapid onset lymphoma without mutational loss of p53. This phenomenon was investigated further by transcriptomic analysis of premalignant thymus from RUNX2/MYC transgenic mice. The distinctive contributions of MYC and RUNX to transcriptional control were illustrated by differential enrichment of canonical binding sites and gene ontology analyses. Pathway analysis revealed signatures of MYC, CD3, and CD28 regulation indicative of activation and proliferation, but also strong inhibition of cell death pathways. In silico analysis of discordantly expressed genes revealed Tnfsrf8/CD30, Cish, and Il13 among relevant targets for sustained proliferation and survival. Although TP53 mRNA and protein levels were upregulated, its downstream targets in growth suppression and apoptosis were largely unperturbed. Analysis of genes encoding p53 posttranslational modifiers showed significant upregulation of three genes, Smyd2, Set, and Prmt5. Overexpression of SMYD2 was validated in vivo but the functional analysis was constrained by in vitro loss of p53 in RUNX2/MYC lymphoma cell lines. However, an early role is suggested by the ability of SMYD2 to block senescence‐like growth arrest induced by RUNX overexpression in primary fibroblasts.

Die Another Day: Inhibition of Cell Death Pathways by Cytomegalovirus.

Multicellular organisms have evolved multiple genetically programmed cell death pathways that are essential for homeostasis. The finding that many viruses encode cell death inhibitors suggested that cellular suicide also functions as a first line of defence against invading pathogens. This theory was confirmed by studying viral mutants that lack certain cell death inhibitors. Cytomegaloviruses, a family of species-specific viruses, have proved particularly useful in this respect. Cytomegaloviruses are known to encode multiple death inhibitors that are required for efficient viral replication. Here, we outline the mechanisms used by the host cell to detect cytomegalovirus infection and discuss the methods employed by the cytomegalovirus family to prevent death of the host cell. In addition to enhancing our understanding of cytomegalovirus pathogenesis we detail how this research has provided significant insights into the cross-talk that exists between the various cell death pathways.

Inhibition of the Cell Death Pathway in Nonalcoholic Steatohepatitis (NASH)-Related Hepatocarcinogenesis Is Associated with Histone H4 lysine 16 Deacetylation

Hepatocellular carcinoma (HCC) is one of the most aggressive human cancers, and its incidence is steadily increasing worldwide. Recent epidemiologic findings have suggested that the increased incidence of HCC is associated with obesity, type II diabetes mellitus, and nonalcoholic steatohepatitis (NASH); however, the mechanisms and the molecular pathogenesis of NASH-related HCC are not fully understood. To elucidate the underlying mechanisms of the development of NASH-related HCC, we investigated the hepatic transcriptomic and histone modification profiles in Stelic Animal Model mice, the first animal model of NASH-related HCC to resemble the disease pathogenesis in humans. The results demonstrate that the development of NASH-related HCC is characterized by progressive transcriptomic alterations, global loss of histone H4 lysine 20 trimethylation (H4K20me3), and global and gene-specific deacetylation of histone H4 lysine 16 (H4K16). Pathway analysis of the entire set of differentially expressed genes indicated that the inhibition of cell death pathway was the most prominent alteration, and this was facilitated by persistent gene-specific histone H4K16 deacetylation. Mechanistically, deacetylation of histone H4K16 was associated with downregulation of lysine acetyltransferase KAT8, which was driven by overexpression of its inhibitor nuclear protein 1 (Nupr1). The results of this study identified a reduction of global and gene-specific histone H4K16 acetylation as a key pathophysiologic mechanism contributing to the development of NASH-derived HCC and emphasized the importance of epigenetic alterations as diagnostic and therapeutic targets for HCC.Implications: Histone H4K16 deacetylation induces silencing of genes related to the cell death that occurred during the development of NASH-related HCC. Mol Cancer Res; 15(9); 1163-72. ©2017 AACR.

Resistance to apoptosis and autophagy leads to enhanced survival in Sertoli cells.

What is the underlying mechanism of Sertoli cell (SC) resistance to cell death? High expression of prosurvival B-cell lymphoma-2 (BCL2) proteins and inhibition of apoptosis and autophagy prolongs SC survival upon exposure to stress stimuli. In human and in experimental models of orchitis, tolerogenic SC survive stress conditions, while germ cells undergo massive apoptosis. In general, non-dividing highly differentiated cells tend to resist stress conditions for a longer time by favoring activation of prosurvival mechanisms and inhibition of cell death pathways. In this cross sectional study, conditions stimulating apoptosis and autophagy were used to induce cell death in primary rat SC. Primary rat peritubular cells (PTC) and immortalized rat 93RS2 SC were used as controls. Each cell isolation was counted as one experiment (n = 1), and each experiment was repeated three to six times. Testis biopsy samples from infertile or subfertile patients and testis samples from rats with experimental autoimmune orchitis were used for immunohistological analysis. Primary SC were isolated from 19-day-old male Wistar rats. To maintain cell purity, cells were cultured in serum-free medium for apoptosis experiments and in medium supplemented with 1% serum for autophagy analyses. To induce apoptosis, cells were stimulated with staurosporine, borrelidin, cisplatin and etoposide for 4 or 24 h. Caspase three activation was examined by immunoblotting and enzymatic activity assay. Mitochondrial membrane potential was measured using tetramethylrhodamine methyl ester followed by flow cytometric analysis. Cytochrome c release was monitored by immunofluorescence. Cell viability was determined using the methylthiazole tetrazolium assay. To monitor autophagy flux, cells were deprived of nutrients using Hank's balanced salt solution for 1, 2 and 3 h. Formation of autophagosomes was analyzed by using immunoblotting, immunofluorescence labeling and ultrastructural analyses. Relative mRNA levels of genes involved in the regulation of apoptosis and autophagy were evaluated. Extracellular high mobility group box protein one was measured as a marker of necrosis using ELISA. SC survive the inflammatory conditions in vivo in human testis and in experimental autoimmune orchitis. Treatment with apoptosis inducing chemotherapeutics did not cause caspase three activation in isolated rat SC. Moreover, mitochondrial membrane potential and mitochondrial localization of cytochrome c were not changed by treatment with staurosporine, suggesting a premitochondrial blockade of apoptosis in SC. Expression levels of prosurvival BCL2 family members were significantly higher in SC compared to PTC at both mRNA and protein levels. Furthermore, after nutrient starvation, autophagy signaling was initiated in SC as observed by decreased levels of phosphorylated UNC- 51-like kinase -1 (ULK1). However, levels of light chain 3 II (LC3 II) and sequestosome1 (SQSTM1) remained unchanged, indicating blockade of the autophagy flux. Lysosomal activity was intact in SC as shown by accumulation of LC3 II following administration of lysosomal protease inhibitors, indicating that inhibition of autophagy flux occurs at a preceding stage. N/A. In this study, we have used primary SC from prepubertal rats. Caution should be taken when translating our results to adult animals, where crosstalk with other testicular cells and hormonal factors may also play a role in regulating survival of SC. Our results suggest that inhibition of autophagy and apoptosis following exposure to extrinsic stress stimuli promotes SC survival, and is a possible mechanism to explain the robustness of SC in response to stress. Cell death resistance in SC is crucial for the recovery of spermatogenesis after chemotherapy treatment in cancer patients. Additionally, understanding the molecular mechanisms of SC survival unravels valuable target proteins, such as BCL2, that may be manipulated therapeutically to control cell viability depending on the context of the disease. This study was funded by the Deutsche Forschungsgemeinschaft (DFG) Grant BH93/1-1, and by the International Research Training Group between Justus Liebig University of Giessen and Monash University, Melbourne (GRK 1871/1) funded by the DFG and Monash University. The support of the Medical Faculty of Justus-Liebig University of Giessen is gratefully acknowledged. The authors declare no conflict of interest.

Epigenetic marks responsible for cadmium-induced melanoma cell overgrowth

Cadmium (Cd) is a human carcinogen that likely acts via epigenetic mechanisms. However, the precise role of Cd in melanoma remains to be defined. The goals of this study are to: (i) examine the effect of Cd on the proliferation rate of cutaneous and uveal melanoma cells; (ii) identify the genes affected by Cd exposure; (iii) understand whether epigenetic changes are involved in the response to Cd. The cell growth capacity increased at 48h after Cd treatment at doses ranging from 0.5 to 10μМ. The research on the key genes regulating proliferation has shown that aberrant methylation is responsible for silencing of p16INK4A and caspase 8 in uveal and cutaneous melanoma cells, respectively. The methylation and expression patterns of p14ARF, death receptors 4/5, and E-cadherin remained unmodified after Cd treatment in all the cell lines analyzed. Ectopic expression of p16INK4A abolished the overgrowth of uveal melanoma cells in response to Cd and the overexpression of caspase 8 drastically increased the apoptotic rate of Cd-treated cutaneous melanoma cells. In conclusion, our data suggest that hypermethylation of p16INK4A and caspase 8 represents the most common event linked to Cd-induced stimulation of cell growth and inhibition of cell death pathway in melanoma.

Development of Small Molecules Activating TRAIL Apoptosis Pathway for Cancer Therapies

It has been thirty-eight years since tumor necrosis factor- (TNF) was isolated and found with cancer therapeutic potential in 1975 [1]; however, all the efforts have failed in the development of TNF and its family ligands as cancer drugs [2] first due to the lethal toxicity of TNF and Fas ligand (FasL) [3,4]. In the middle 1990s, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL; Apo2 ligand, Apo2L) was identified as a member of the TNF ligand family [5,6] that can induce apoptosis in cancer cells without the toxicity as caused by TNF and FasL [7,8], leading to renewed efforts in development of this TNF family ligand as a cancer therapeutic. TRAIL is a type II membrane protein that is normally expressed on the surface of immune cells in execution of innate and adaptive immunity against cancers in immunosurveillance [9]. TRAIL has a short intracellular N-terminal tail and a long extracellular C-terminal with the receptor-binding domain [10]; thus, recombinant human TRAIL (rhTRAIL) of the C-terminal has been generated as a cancer drug (rhApoL/TRAIL; dulanermin). Phase I trials approved the safety of rhTRAIL in patients [11,12]; however, phase II trial revealed the drug resistance of human solid cancers [13]. TRAIL-induced apoptosis occurs through the binding of its cognate receptors, TRAIL receptor 1 (TRAIL-R1; death receptor 4, DR4) and TRAIL-R2 (DR5) on the surface of cancer cells; DR4 and DR5 become trimerized and recruit intracellular Fas-associate death domain (FADD) and apoptosis-initiating caspase-8 in assembly of a death-inducing signaling complex (DISC), where caspase-8 is dimerized, cleaved and activated in the initiation of the extrinsic apoptotic pathway [2]. In addition, caspase-8 enzymes cleave the Bid and activate the intrinsic mitochondrial pathway with the release of the apoptotic proteins including the second mitochondrial-derived activator of caspases (Smac). To target DR5, a mouse monoclonal antibody against human DR5 (TRA-8) was generated for antitumor activity but no hepatotoxicity [14]. This DR5 agonistic mouse monoclonal antibody was humanized as a therapeutic (CS-1008; tigatuzumab) [15] and passed the safety evaluation in a phase I trial [16]. Advances in antibody technology led to the generation of fully human monoclonal antibodies against DR4 and DR5 for activation of TRAIL apoptotic pathway in cancer cells [17]. Phase I trials evaluated the safety of the DR4 agonistic antibody HGS-ETR1 (mapatumumab), the DR5 agonistic antibodies HGS-ERT2 (lexatumumab) and PRO95780 (drozitumab) [18-20]. Once again, however, phase II trials failed to show clinical anticancer activity of HGS-ETR1 [21,22] and PRO95780, as reported at the 2010 Annual Meeting of the American Society of Clinical Oncology. Cleary, the drug resistance now is the roadblock in development of TRAIL agonists as cancer drugs. TRAIL is a natural cancer killer in immunosurveillance [9]; however, this notion also predicts that cancer occurs in patients by evasion of TRAIL-mediated immunity; thus, the drug resistance is the inherent nature of cancer. Cancer is a genetic disease and genetic alterations lead to its relentless growth through activation of growth pathways such as phosphatidylinositide-3-kinase (PI3K), AKT and extracellular signal-regulated kinase (ERK) on the one hand and inhibition of cell death pathways on the other hand; thus, current efforts are focused on the development of combination therapies that can block cell growth and activate cell death pathways in cancer cells [2]. From the pharmacokinetic point of view, however, rhTRAIL protein and DR4/DR5 agonistic antibodies as drugs suffer from short half-life and poor tissues distribution. To overcome these limits of protein-drugs, researchers have turned their attention to high-throughput drug screening for small molecules that can activate TRAIL apoptotic pathway in cancer cells. Biochemical and cell-based assays are the two mainstays in high-through drug screening; yet, cell-based assays are used more now because they represent specific responses of targeted cells. Published in the February

Small heat shock proteins in cancer therapy and prognosis

Hsp27 and clusterin (CLU are stress-activated small heat shock proteins that are up-regulated in many cancers where they play important roles in stress-induced protein homeostasis (proteostasis), inhibition of cell death pathways, and modulation of pro-survival signaling and transcriptional networks. They are associated with poor prognosis and treatment resistance in many cancers, protecting cells from many varied therapeutic stressors that induce apoptosis, including androgen or estrogen withdrawal, radiation, cytotoxic chemotherapy, and biologic agents. Both Hsp27 and sCLU are ATP-independent molecular chaperones making them less amenable to inhibition by small molecules, and so strategies to inhibit Hsp27 and sCLU at the gene-expression level are appealing. Indeed, known nucleotide sequences of cancer-relevant genes offer the possibility to rapidly design antisense oligonucleotides (ASO) for loss-of-function and preclinical proof-of-principle studies and subsequent clinical use. Here, we will review the rationale for Hsp27 and sCLU as therapeutic targets in cancer, and update the current status of pre-clinical and clinical studies using Hsp27 and CLU inhibitors, OGX-427 and OGX-011, respectively.This article is part of a Directed Issue entitled: Small HSPs in physiology and pathology.

Harnessing Tumor Necrosis Factor Receptors to Enhance Antitumor Activities of Drugs

Cancer is the second-leading cause of death in the U.S. behind heart disease and over stroke. The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The inhibition of cell death pathways is one of these tumor characteristics which also include sustained proliferative signaling, evading growth suppressor signaling, replicative immortality, angiogenesis, and promotion of invasion and metastasis. Cell death is mediated through death receptor (DR) stimulation initiated by specific ligands that transmit signaling to the cell death machinery or through the participation of mitochondria. Cell death involving DR is mediated by the superfamily of tumor necrosis factor receptor (TNF-R) which includes TNF-R type I, CD95, DR3, TNF-related apoptosis-inducing ligand (TRAIL) receptor-1 (TRAIL-R1) and -2 (TRAIL-R2), DR6, ectodysplasin A (EDA) receptor (EDAR), and the nerve growth factor (NGF) receptor (NGFR). The expression of these receptors in healthy and tumor cells induces treatment side effects that limit the systemic administration of cell death-inducing therapies. The present review is focused on the different therapeutic strategies such as targeted antibodies or small molecules addressed to selective stimulated DR-mediated apoptosis or reduce cell proliferation in cancer cells.

Recombinant human prolactin promotes human beta cell survival via inhibition of extrinsic and intrinsic apoptosis pathways

Transplantation of pancreatic islets constitutes a promising alternative treatment for type 1 diabetes. However, it is limited by the shortage of organ donors. Previous results from our laboratory have demonstrated beneficial effects of recombinant human prolactin (rhPRL) treatment on beta cell cultures. We therefore investigated the role of rhPRL action in human beta cell survival, focusing on the molecular mechanisms involved in this process. Human pancreatic islets were isolated using an automated method. Islet cultures were pre-treated in the absence or presence of rhPRL and then subjected to serum starvation or cytokine treatment. Beta cells were labelled with Newport green and apoptosis was evaluated using flow cytometry analysis. Levels of BCL2 gene family members were studied by quantitative RT-PCR and western blot. Caspase-8, -9 and -3 activity, as well as nitric oxide production, were evaluated by fluorimetric assays. The proportion of apoptotic beta cells was significantly lowered in the presence of rhPRL under both cell death-induced conditions. We also demonstrated that cytoprotection may involve an increase of BCL2/BAX ratio, as well as inhibition of caspase-8, -9 and -3. Our study provides relevant evidence for a protective effect of lactogens on human beta cell apoptosis. The results also suggest that the improvement of cell survival may involve, at least in part, inhibition of cell death pathways controlled by the BCL2 gene family members. These findings are highly relevant for improvement of the islet isolation procedure and for clinical islet transplantation.

The injured eye

Eye injuries come at a high cost to society and are avoidable. Ocular blast injuries can be primary, from the blast wave itself; secondary, from fragments carried by the blast wind; tertiary; due to structural collapse or being thrown against a fixed object; or quaternary, from burns and indirect injuries. Ballistic eye protection significantly reduces the incidence of eye injuries and should be encouraged from an early stage in Military training. Management of an injured eye requires meticulous history taking, evaluation of vision that measures the acuity and if there is a relative pupillary defect as well as careful inspection of the eyes, under anaesthetic if necessary. A lateral canthotomy with cantholysis should be performed immediately if there is a sight-threatening retrobulbar haemorrhage. Systemic antibiotics should be prescribed if there is a suspected penetrating or perforating injury. A ruptured globe should be protected by an eye shield. Primary repair of ruptured globes should be performed in a timely fashion. Secondary procedures will often be required at a later date to achieve sight preservation. A poor initial visual acuity is not a guarantee of a poor final result. The final result can be predicted after approximately 3-4 weeks. Future research in eye injuries attempts to reduce scarring and neuronal damage as well as to promote photoreceptor rescue, using post-transcriptional inhibition of cell death pathways and vaccination to promote neural recovery. Where the sight has been lost sensory substitution of a picture from a spectacle mounted video camera to the touch receptors of the tongue can be used to achieve appreciation of the outside world.

Transpupillary thermotherapy: New observations on neuroprotection of retinal ganglion cells

ranspupillary thermotherapy (TTT) is a technique in which heat s delivered to the posterior segment of the eye through the pupil sing a modified low power diode laser with a broad beam. This ethod uses infrared radiation to increase the temperature in the reated tissue up to 10 ◦C above baseline levels and it is been tried or the treatment of various intraocular tumors and choroidal neoascularization in age-related macular degeneration [7]. However, he bulk of clinical data regarding TTT yields mixed results and furher studies are need to demonstrate that improvements in health utcomes occur with acceptable levels of adverse effects. Recently several neuroscientists using the visual system as a odel to study degenerative disorders in the central nervous sysem (CNS) have turned their attention to the potential possibilities f this technique to treat some retinal neurodegenerative diseases. n CNS it is well establish that in response to physiological, pathoogical or environmental stress, neurons and glial cells activate the eat shock response inwhich a set of heat shock proteins (HSPs) are nduced, playing important roles in cellular repair and protective echanisms [1]. It is though that an increase in protein damage an trigger this response, and available studies suggest that HSPs re important in the refolding of partially denatured proteins, the revention of protein aggregation, the reduction of inflammatory esponses and the inhibition of cell death pathways [1–3,6]. These bservations point out to HSPs as multifaceted proteins that proect injured neurons from severe damage and allow resumption of ormal cellular and physiological activities through a wide variety f mechanisms.

Overexpression of Heat Shock Protein 27 Reduces Cortical Damage after Cerebral Ischemia

Heat shock protein 27 (HSP27) has a major role in mediating survival responses to a range of central nervous system insults, functioning as a protein chaperone, an antioxidant, and through inhibition of cell death pathways. We have used transgenic mice overexpressing HSP27 (HSP27tg) to examine the role of HSP27 in cerebral ischemia, using model of permanent middle cerebral artery occlusion (MCAO). Infarct size was evaluated using multislice T(2)-weighted anatomical magnetic resonance imaging (MRI) after 24 h. A significant reduction of 30% in infarct size was detected in HSP27tg animals compared with wild-type (WT) littermates. To gain some insight into the mechanisms contributing to cell death and its attenuation by HSP27, we monitored the effect of induction of c-jun and ATF3 on tissue survival in MCAO and their effects on the expression of endogenous mouse HSP25 and HSP70. It is important that, the c-jun induction seen at 4 h tended to be localized to regions that were salvageable in HSP27tg mice but became infarcted in WT animals. Our results provide support for the powerful neuroprotective effects of HSP27 in cerebral ischemia.

Programmed cell death during animal development.

The formation of the hand during embryogenesis, the peeling of sunburned skin and the tremor associated with Parkinson's disease all result from a common process: cell death. Cell death occurs throughout the life span of the organism and represents the ultimate differentiative decision made by cells. Insight into the process of cell death will not only contribute to our understanding of basic developmental issues, but will also facilitate the development of therapeutic interventions that could alter the course of disease. Since all cells have the genetic machinery required to commit suicide, the ability to initiate it in a lineage-specific, non-inflammatory manner would allow for the irradication of specific cancers. Alternatively, inhibition of cell death pathways could rescue valuable but condemned cells, such as HIV infected CD4+ T cells or dopaminergic neurons in Parkinson's disease. The goal of this chapter is to provide both an overview of the basic principles that govern the cellular and molecular mechanisms mediating cell death, as well as serve as a reference of known examples of PCD and the genes that mediate this process.