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1.
The cellular mechanisms underlying hereditary photoreceptor degeneration are still poorly understood, a problem that is exacerbated by the enormous genetic heterogeneity of this disease group. However, the last decade has yielded a wealth of new knowledge on degenerative pathways and their diversity. Notably, a central role of cGMP-signalling has surfaced for photoreceptor cell death triggered by a subset of disease-causing mutations.In this review, we examine key aspects relevant for photoreceptor degeneration of hereditary origin. The topics covered include energy metabolism, epigenetics, protein quality control, as well as cGMP- and Ca2+-signalling, and how the related molecular and metabolic processes may trigger photoreceptor demise. We compare and integrate evidence on different cell death mechanisms that have been associated with photoreceptor degeneration, including apoptosis, necrosis, necroptosis, and PARthanatos. A special focus is then put on the mechanisms of cGMP-dependent cell death and how exceedingly high photoreceptor cGMP levels may cause activation of Ca2+-dependent calpain-type proteases, histone deacetylases and poly-ADP-ribose polymerase. An evaluation of the available literature reveals that a large group of patients suffering from hereditary photoreceptor degeneration carry mutations that are likely to trigger cGMP-dependent cell death, making this pathway a prime target for future therapy development.Finally, an outlook is given into technological and methodological developments that will with time likely contribute to a comprehensive overview over the entire metabolic complexity of photoreceptor cell death. Building on such developments, new imaging technology and novel biomarkers may be used to develop clinical test strategies, that fully consider the genetic heterogeneity of hereditary retinal degenerations, in order to facilitate clinical testing of novel treatment approaches. 相似文献
2.
A. Nakao H. Toyokawa A. Tsung M. A. Nalesnik D. B. Stolz J. Kohmoto A. Ikeda K. Tomiyama T. Harada T. Takahashi R. Yang M. P. Fink K. Morita A. M. K. Choi N. Murase 《American journal of transplantation》2006,6(10):2243-2255
Carbon monoxide (CO), a byproduct of heme catalysis, was shown to have potent cytoprotective and anti-inflammatory effects. In vivo recipient CO inhalation at low concentrations prevented ischemia/reperfusion (I/R) injury associated with small intestinal transplantation (SITx). This study examined whether ex vivo delivery of CO in University of Wisconsin (UW) solution could ameliorate intestinal I/R injury. Orthotopic syngenic SITx was performed in Lewis rats after 6 h cold preservation in control UW or UW that was bubbled with CO gas (0.1-5%) (CO-UW). Recipient survival with intestinal grafts preserved in 5%, but not 0.1%, CO-UW improved to 86.7% (13/15) from 53% (9/17) with control UW. At 3 h after SITx, grafts stored in 5% CO-UW showed improved intestinal barrier function, less mucosal denudation and reduced inflammatory mediator upregulation compared to those in control UW. Preservation in CO-UW associated with reduced vascular resistance (end preservation), increased graft cyclic guanosine monophosphate levels (1 h), and improved graft blood flow (1 h). Protective effects of CO-UW were reversed by ODQ, an inhibitor of soluble guanylyl cyclase. In vitro culture experiment also showed better preservation of vascular endothelial cells with CO-UW. The study suggests that ex vivo CO delivery into UW solution would be a simple and innovative therapeutic strategy to prevent transplant-induced I/R injury. 相似文献
3.
本文对14例体外循环下心内直视手术病人采用放免法,于不同时段测定体外循环转流期间血浆的环核苷酸cAMP 和cGMP 变化。结果表明,在体外循环期间,cAMP和cGMP 浓度进行性上升,转流结束时达到最高峰,随着自身循环的恢复,cAMP 和cGNP浓度逐渐下降,术后次日恢复到术前水平;而cAMP/cGMP 比值在体外循环期间无明显变化。文中讨论了cAMP 和cGMP 变化的机制和临床意义。 相似文献
4.
Linkage studies and mutation analysis of the PDEB gene in 23 families with Leber congenital amaurosis. 总被引:1,自引:0,他引:1
The phenotype in the rd mouse is similar to the clinical presentation of Leber congenital amaurosis (LCA) in humans. Recently a nonsense mutation in the beta subunit of the cGMP phosphodiesterase (Pdeb) gene has been defined as the cause for the rd phenotype in the mouse and has raised the question as to whether mutations in the human PDEB gene might cause LCA. We have previously cloned and characterized the human homologue of the mouse Pdeb gene and have mapped it to chromosome 4p16.3. In this study, a total of 23 LCA families of various ethnic backgrounds have been investigated. Linkage analysis using highly polymorphic (CA)n microsatellites has excluded the PDEB gene as a cause for LCA in 6 families. In the remaining 17 families, we have searched for mutations in the 22 exons of the PDEB gene using single-strand gel electrophoresis (SSGE). Multiple exonic polymorphisms have been determined. However, no DNA changes in the PDEB gene have been identified in our study population which could be causative for the LCA phenotype. 相似文献
5.
6.
Dystonia is a common movement disorder which is thought to represent a disease of the basal ganglia. However, the pathogenesis of the idiopathic dystonias, i.e. the neuroanatomic and neurochemical basis, is still a mystery. Research in dystonia is complicated by the existence of various phenotypic and genotypic subtypes of idiopathic dystonia, probably related to heterogeneous dysfunctions.In neurological diseases in which no obvious neuronal degeneration can be found, such as in idiopathic dystonia, the identification of a primary defect is difficult, because of the large number of chemically distinct, but functionally interrelated, neurotransmitter systems in the brain.The variable response to pharmacological agents in patients with idiopathic dystonia supports the notion that the underlying biochemical dysfunctions vary in the subtypes of idiopathic dystonia. Hence, in basic research it is important to clearly define the involved type of dystonia.Animal models of dystonias were described as limited. However, over the last years, there has been considerable progress in the evaluation of animal models for different types of dystonia.Apart from animal models of symptomatic dystonia, genetic animal models with inherited dystonia which occurs in the absence of pathomorphological alterations in brain and spinal cord are described.This review will focus mainly on genetic animal models of different idiopathic dystonias and pathophysiological findings. In particular, in the case of the mutant dystonic (dt) rat, a model of generalized dystonia, and in the case of the genetically dystonic hamster (dtsz), a model of paroxysmal dystonic choreoathetosis has been used, as these show great promise in contributing to the identification of underlying mechanisms in idiopathic dystonias, although even a proper animal model will probably never be equivalent to a human disease.Several pathophysiological findings from animal models are in line with clinical observations in dystonic patients, indicating abnormalities not only in the basal ganglia and thalamic nuclei, but also in the cerebellum and brainstem. Through clinical studies and neurochemical data several similarities were found in the genetic animal models, although the current data indicates different defects in dystonic animals which is consistent with the notion that dystonia is a heterogenous disorder.Different supraspinal dysfunctions appear to lead to manifestation of dystonic movements and postures. In addition to increasing our understanding of the pathophysiology of idiopathic dystonia, animal models may help to improve therapeutic strategies for this movement disorder. 相似文献
7.
8.
R. Sten K. Lossius A.A. Persson J.O.G Karlsson 《Acta physiologica (Oxford, England)》2001,171(1):29-35
Mechanisms mediating endothelium‐dependent vasodilation were investigated in femoral artery rings from <2‐day‐old (newborn) and 2‐week‐old piglets. Based on previous results we hypothesized an age difference in the relative contribution of nitric oxide(NO)‐cyclic 3′,5′‐guanosine monophosphate (cGMP) and K+ channel‐activation to acetylcholine (ACh)‐induced vasodilation. Changes in vascular tone were studied in organ baths in the absence or presence of NO synthase(NOS) inhibition or K+ channel blockade and the intra‐arterial accumulation of cGMP in response to ACh was measured with radioimmunoassay (RIA). In control experiments, relaxant responses to ACh were equal in the two age groups. In the presence of the NOS‐inhibitors N G‐monomethyl‐L ‐arginine acetate (L ‐NMMA; 100 μM ) or NG‐nitro‐L ‐arginine (L ‐NOARG; 1–100 μM ), however, relaxation was significantly more reduced in femoral artery rings from 2‐week‐old than from newborn, with lower pD2 values in the older age group. Inhibition of large (BKCa) conductance calcium‐sensitive K+ channels with tetraethylammonium chloride (TEA; 1 mM ), gave a significant rightward shift in the concentration‐response curves to ACh which was of the same magnitude in both age groups. The ACh‐induced vasodilation was abolished in both age groups by high K+ (20 mM ) in combination with L ‐NOARG (100 μM ). The relative increase in cGMP levels after addition of ACh (10 nM ) was significantly larger in rings from newborn compared with 2‐week‐old piglets (12‐ vs. four‐fold). In summary, sensitivity to NOS inhibition increased with age while the effect of K+ channel blockade with TEA was the same in femoral artery rings from newborn to 2‐week‐old piglets. Lower sensitivity to NOS inhibition and a larger increase in cGMP in response to ACh could indicate a higher efficacy of the NO/cGMP pathway in this vessel in the newborn piglet. 相似文献
9.
Kapilevich LV Nosarev AV Kovalev IV D'yakova EY Baskakov MB 《Bulletin of experimental biology and medicine》2003,135(6):610-612
The involvement of cAMP- and cGMP-dependent signal systems into the regulation of the contractile reaction of smooth muscles of the rabbit pulmonary arteries was studied using a mechanographic method. For modulation of intracellular level of cyclic nucleotides we used adenylate cyclase activators -adrenoceptor agonist isadrin, guanylate cyclase inhibitor methylene blue, penetrating analog dibutyryl-cAMP, and phosphodiesterase inhibitors. The mechanisms of cAMP- and cGMP-dependent regulation of smooth muscle contractile activity were realized in close interrelationship, and the key component of this was cyclic nucleotide phosphodiesterases. The ratio of activities of phosphodiesterase subtypes in smooth-muscle cells can essentially modulate the adrenergic effects in the pulmonary artery wall and even invert them. 相似文献
10.
We studied the effect of the nitric oxide (NO) donor, sodium nitroprusside (SNP), on the macroscopic and single-channel currents
due to the 22-pS Ca2+ channel in smooth muscle cells from guinea pig basilar artery. In nystatin-perforated whole-cell recordings, 50 nM SNP decreased
the macroscopic current to 63±12% of control values, without changing the voltage dependence of the current. In cell-attached
patches with BAY-K8644 in the pipette, SNP caused a comparable decrease in single-channel availability (n ·P
o) that was dose dependent over the range of 10 nM to 10 μM SNP. SNP had no effect on single-channel properties, including
slope conductance, voltage dependence of activation, the number of open states, the time constants of the open states, and
the proportion of time spent in each open state. The effect of SNP (50 nM) on single Ca2+ channel openings was reproduced by 8-Br-cGMP (100 μM), which also reduced channel availability without altering channel properties.
The protein kinase inhibitor H-8 (1.5 μM), which exhibits relative specificity for cGMP-dependent protein kinase, completely
inhibited the decrease in single-channel availability expected with SNP. The dose-dependent decrease in Ca2+ channel availability caused by SNP was not altered by prior application of 8-Br-cAMP or forskolin, both of which cause an
increase in Ca2+ channel availability in these cells. Our findings suggest that NO decreases openings of Ca2+ channels in basilar artery smooth muscle cells without altering channel properties, and that it does so by a mechanism likely
to involve cGMP-dependent protein kinase.
Received: 2 July 1996 / Received after revision: 30 September 1996 / Accepted: 2 October 1996 相似文献