Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hereditary spinocerebellar ataxia with axonal neuropathy (SCAN1) is caused by an inactivating mutation (H493R) in the enzyme tyrosyl-DNA phosphodiesterase (Tdp1), which removes blocked 3'-termini at DNA strand breaks. Using SCAN1 cells treated with the specific topoisomerase I (Top1) inhibitor camptothecin, we find enhanced levels of Top1 cleavage complexes (Top1cc) and defective reversal of Top1cc in SCAN1 Tdp1-deficient cells, indicating a direct involvement of Tdp1 in the repair of Top1cc. Because the defective removal of Top1cc and the hypersensitivity of SCAN1 cells to camptothecin are not affected by aphidicolin, we propose that Tdp1 is involved in the repair of Top1cc associated with transcription damage in SCAN1 cells.
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PMID:Hereditary ataxia SCAN1 cells are defective for the repair of transcription-dependent topoisomerase I cleavage complexes. 1693 73

DNA single-strand breaks (SSBs) are the commonest DNA lesions arising spontaneously in cells, and if not repaired may block transcription or may be converted into potentially lethal/clastogenic DNA double-strand breaks (DSBs). Recently, evidence has emerged that defects in the rapid repair of SSBs preferentially impact the nervous system. In particular, spinocerebellar ataxia with axonal neuropathy (SCAN1) is a human disease that is associated with mutation of TDP1 (tyrosyl DNA phosphodiesterase 1) protein and with a defect in repairing certain types of SSBs. Although SCAN1 is a rare neurodegenerative disorder, understanding the molecular basis of this disease will lead to better understanding of neurodegenerative processes. Here we review recent progress in our understanding of TDP1, single-strand break repair (SSBR), and neurodegenerative disease.
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PMID:DNA single-strand break repair and spinocerebellar ataxia with axonal neuropathy-1. 1704 54

Erectile dysfunction (ED) affects up to 50% of men between the ages of 40 and 70 years of age. Sildenafil, vardenafil and tadalafil have all been shown to be similarly effective in the treatment of men with ED of vary etiologies, to have similar adverse effects profiles, and to improve quality-of-life by similar amounts. As these phosphodiesterase 5 (PDE5) inhibitors all increase the hypotensive effects of nitrates, they are not suitable for use in patients taking nitrates for the treatment of ischaemic heart disease. All three inhibitors must be used with caution in patients taking alpha(1)-adrenoceptors antagonists for benign prostatic hyperplasia. Although nonarteritic anterior ischaemic neuropathy has been reported in some users of the PDE5 inhibitors, there is no conclusive evidence that PDE5 inhibitors cause this rare effect. Tadalafil has a longer half-life than sildenafil or vardenafil, and a longer duration of action than sildenafil and vardenafil. Most preference studies have shown tadalafil to be preferred, but there are serious limitations to some of these studies. One approach to treatment is to give each patient a short- and long-acting agent, and for individuals to decide their preference.
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PMID:Do vardenafil and tadalafil have advantages over sildenafil in the treatment of erectile dysfunction? 1718 46

Sildenafil citrate is a specific inhibitor of phosphodiesterase (PDE) type-5 and represents a powerful therapy for male erectile and fertility dysfunctions of different etiologies. Present study demonstrates whether sildenafil administration modifies seminal parameters in diabetic neuropathic patients. In this investigation 50 insulin dependent (IDDM) and 50 non insulin dependent (NIDDM) diabetic male patients with and without an objective evidence of neuropathy and 50 age matched non diabetic male controls were selected. Every male had age between 20 to 65 years with duration of diabetes distributed over 1 to 20 years. Treatment with 100 mg of oral sildenafil citrate on seminal parameters was evaluated by semen analysis in these patients. In both IDDM and NIDDM diabetic neuropathic patients, chronic sildenafil treatment exhibited a significant decrease in total sperm output and sperm concentration (p<0.001). On the other hand, sperm motility and semen volume were found to be increased by about 40% and 48% respectively in these patients, where as sperm morphology and quality of sperm motility remained unaffected. However both types of non neuropathic diabetics showed a non significant difference in all the above mentioned parameters when compared with the untreated groups and their respective control subjects. A comparison between IDDM and NIDDM neuropathic and non neuropathic diabetic groups further indicated a non significant difference in all the parameters of semen analysis. These findings suggest a chronic neuro physiological effect of sildenafil treatment on male fertility profile exclusively in diabetic neuropathic condition with an improvement in testicular function which was probably arrested due to some kind of testicular hyperplasia resulted by testicular necrosis and promoted spermatogenesis. Sildenafil seems to be associated with an improvement in the entire smooth musculature of reproductive tract and testicular morphology which was altered due to neuropathy like a reduction in excess accumulation of interstitial collagen and calcification in the smooth muscles of seminiferous tubules which made them rigid leading to atonia of bladder and urethra which resulted in partial or retrograde ejaculation associated with a decreased sperm motility. Sildenafil treatment returned back the spermatogenesis to normal with a positive influence on sperm motility and ejaculate volume in these neuropathic patients irrespective of the type of diabetes.
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PMID:Neurophysiological role of sildenafil citrate (Viagra) on seminal parameters in diabetic males with and without neuropathy. 1733 26

Nonarteritic anterior ischemic optic neuropathy (NAION) is the most common acute optic neuropathy and one of the most common causes of sudden vision loss in the elderly. Recently, NAION has been associated with the use of phosphodiesterase type 5 inhibitors (PDE5i) in men with erectile dysfunction (ED). A causal relationship could not be established given the large number of men safely using PDE5i and the limited number of NAION cases reported in these men. ED and NAION share common risk factors; therefore, some men with ED should be expected to develop NAION. However, sudden vision loss or decreased vision in one or both eyes demands immediate cessation of PDE5i use and urgent patient assessment. No causal relationship between PDE5i and the development of NAION exists for the moment, yet physicians should be aware of a possible adverse reaction and inform patients accordingly.
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PMID:Phosphodiesterase type 5 inhibitors, visual changes, and nonarteritic anterior ischemic optic neuropathy: is there a link? 1804 29

Cilostazol, a selective phosphodiesterase type III inhibitor, has vasodilatory, antiplatelet, and antithrombotic actions, as well as being the first-choice drug for the intermittent claudication due to peripheral vascular disease. Main researches have demonstrated significant improvement for this situation, including patients with diabetes mellitus, concerning pain-free walking distance and quality-of-life, not rising the bleeding event risk. It does not affect the glucose metabolism even in patients suffering from diabetes. This paper aims to present a review on the discoveries of various studies, most of them experimental, on the prevention and treatment of diabetes mellitus complications, such as nephropathy and neuropathy, through the use of cilostazol, which demonstrated satisfactory results on the improvement in neural blood flow, on sodium-potassium ATPase activity, on insulin resistance, and microalbuminuria. However, strict controlling of glucose plasma levels, hypertension, and smoking habits, as well as more extended investigations on the matter are required to the better comprehension.
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PMID:[Potential therapeutic approaches for prevention and treatment of diabetic nephropathy and neuropathy: evidences of cilostazol]. 1820 97

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a recently discovered enzyme that catalyzes the hydrolysis of 3'-phosphotyrosyl bonds. Such linkages form in vivo following the DNA processing activity of topoisomerase I (Top1). For this reason, Tdp1 has been implicated in the repair of irreversible Top1-DNA covalent complexes, which can be generated by either exogenous or endogenous factors. Tdp1 has been regarded as a potential therapeutic co-target of Top1 in that it seemingly counteracts the effects of Top1 inhibitors, such as camptothecin and its clinically used derivatives. Thus, by reducing the repair of Top1-DNA lesions, Tdp1 inhibitors have the potential to augment the anticancer activity of Top1 inhibitors provided there is a presence of genetic abnormalities related to DNA checkpoint and repair pathways. Human Tdp1 can also hydrolyze other 3'-end DNA alterations including 3'-phosphoglycolates and 3'-abasic sites indicating it may function as a general 3'-DNA phosphodiesterase and repair enzyme. The importance of Tdp1 in humans is highlighted by the observation that a recessive mutation in the human TDP1 gene is responsible for the inherited disorder, spinocerebellar ataxia with axonal neuropathy (SCAN1). This review provides a summary of the biochemical and cellular processes performed by Tdp1 as well as the rationale behind the development of Tdp1 inhibitors for anticancer therapy.
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PMID:Tyrosyl-DNA phosphodiesterase as a target for anticancer therapy. 1847 23

Damage of the optic nerve (optic neuropathy) may be caused, apart from other reasons, by an adverse drug effect. The drugs most often discussed in this context are amiodarone, ethambutol, linezolid, and phosphodiesterase inhibitors. By far the most frequent cases appear with ethambutol and may be irreversible. All drugs mentioned here are highly effective in their indications, and their value shall not be questioned by the discussion on a possible damage of the optic nerve. Rather, the knowledge of this side effect shall enhance the responsible handling of drugs and permit a qucker recognition and reaction in case of an optic neuropathy.
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PMID:[Adverse effect optic neuropathy]. 1866 11

In humans, a mutation in the tyrosyl-DNA phosphodiesterase (Tdp1) is responsible for the recessively inherited syndrome spinocerebellar ataxia with axonal neuropathy (SCAN1). Tdp1 is a well-conserved DNA repair enzyme, which processes modified 3' phospho-DNA adducts in vitro. Here, we report that in the yeast Schizosaccharomyces pombe, tdp1 mutant cells progressively accumulate DNA damage and rapidly lose viability in a physiological G0/quiescent state. Remarkably, this effect is independent of topoisomerase I function. Moreover, we provide evidence that Tdp1, with the polynucleotide kinase (Pnk1), processes the same naturally occurring 3'-ends, produced from oxidative DNA damage in G0. We also found that one half of the dead cells lose their nuclear DNA. Nuclear DNA degradation is genetically programmed and mainly depends on the two DNA damage checkpoint responses, ATM/Tel1 and ATR/Rad3, reminiscent to programmed cell death. Diminishing the respiration rate or treating cells with a low concentration of antioxidants rescues the quiescent tdp1 mutant cells. These findings suggest that mitochondrial respiration causes neuronal cell death in the SCAN1 syndrome and in other neurological disorders.
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PMID:Tdp1 protects against oxidative DNA damage in non-dividing fission yeast. 1919 39

A homozygous H493R mutation in the active site of tyrosyl-DNA phosphodiesterase (TDP1) has been implicated in hereditary spinocerebellar ataxia with axonal neuropathy (SCAN1), an autosomal recessive neurodegenerative disease. However, it is uncertain how the H493R mutation elicits the specific pathologies of SCAN1. To address this question, and to further elucidate the role of TDP1 in repair of DNA end modifications and general physiology, we generated a Tdp1 knockout mouse and carried out detailed behavioral analyses as well as characterization of repair deficiencies in extracts of embryo fibroblasts from these animals. While Tdp1(-/-) mice appear phenotypically normal, extracts from Tdp1(-/-) fibroblasts exhibited deficiencies in processing 3'-phosphotyrosyl single-strand breaks and 3'-phosphoglycolate double-strand breaks (DSBs), but not 3'-phosphoglycolate single-strand breaks. Supplementing Tdp1(-/-) extracts with H493R TDP1 partially restored processing of 3'-phosphotyrosyl single-strand breaks, but with evidence of persistent covalent adducts between TDP1 and DNA, consistent with a proposed intermediate-stabilization effect of the SCAN1 mutation. However, H493R TDP1 supplementation had no effect on phosphoglycolate (PG) termini on 3' overhangs of double-strand breaks; these remained completely unprocessed. Altogether, these results suggest that for 3'-phosphoglycolate overhang lesions, the SCAN1 mutation confers loss of function, while for 3'-phosphotyrosyl lesions, the mutation uniquely stabilizes a reaction intermediate.
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PMID:In vitro complementation of Tdp1 deficiency indicates a stabilized enzyme-DNA adduct from tyrosyl but not glycolate lesions as a consequence of the SCAN1 mutation. 1921 12


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