Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ejaculated spermatozoa, particularly in infertile men, have been shown to display morphological and biochemical features that are typical of an apoptotic phenotype in somatic cells. Deregulation of apoptosis is known to play roles in a number of disease processes, but roles for apoptosis in ejaculated spermatozoa and male infertility are poorly defined or have not been studied. Preliminary data demonstrated that populations of ejaculated spermatozoa express: (i) various degrees of plasma membrane translocation of phosphatidylserine and DNA fragmentation; and (ii) active caspase-3, the main executor of apoptosis in somatic cells, with an apparent exclusive cellular location to the mid-piece. Tests are currently being carried out on the effects of well-known apoptosis agonists and caspase inhibitors on such markers using purified populations of leukocyte-free ejaculated human spermatozoa. The main objective is to determine if somatic cell apoptosis markers are relevant indicators and/or causative factors of male infertility.
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PMID:Presence and significance of somatic cell apoptosis markers in human ejaculated spermatozoa. 1465 10

Apoptosis is characterized by a variety of changes resulting in the recognition and phagocytosis of apoptotic cells. Caspases (cysteinyl aspartate-specific proteinases) play a central role in the regulation of apoptosis in the human seminiferous epithelium. They are expressed as inactive proenzymes and participate in a cascade triggered in response to pro-apoptotic signals. To date, 14 caspases have been implicated in the human apoptotic pathway cascade. Among these, caspase-3 is considered to be a major executioner protease. Since apoptosis is a universal suicide system in almost all cells, a close control via molecular, endocrine and physical factors establishes homeostasis of cell growth and death. The proper regulation of the caspase cascade plays an important role in sperm differentiation and testicular maturity. However, caspases have been implicated in the pathogenesis of multiple andrological pathologies such as impaired spermatogenesis, decreased sperm motility and increased levels of sperm DNA fragmentation, testicular torsion, varicocele and immunological infertility. Future research may provide a better understanding of the regulation of caspases, which may help us to manipulate the apoptotic machinery for therapeutic benefits. In this review, we summarize the consequences of caspase activation, aiming to clarify their role in the pathogenesis of male infertility.
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PMID:Role of caspases in male infertility. 1500 63

Oxidative stress has been linked with apoptosis in germ cells and with male infertility. However, the molecular mechanism of oxidative-stress-mediated apoptosis in germ cells has not been clearly defined so far. Because of the involvement of CDC2 and cyclin B1 in cell cycle regulation and their plausible role in apoptosis, the present study aimed to investigate the possibility that selenium (Se)-induced oxidative-stress-mediated modulations of these cell cycle regulators cause DNA damage and apoptosis in germ cells. To create different Se status (deficient, adequate and excess), male Balb/c mice were fed yeast-based Se-deficient diet (Group I) and a deficient diet supplemented with Se as sodium selenite (0.2 and 1 ppm Se in Groups II and III, respectively) for a period of 8 weeks. After the completion of the diet feeding schedule, a significant decrease in Se levels and glutathione peroxidase activity was observed in the Se-deficient group (Group I), whereas the Se-excess group (Group III) demonstrated an increase in Se levels. Increased levels of lipid peroxidation were seen in both Groups I and III when compared to Group II, indicating oxidative stress. The mRNA and protein expressions of both CDC2 and cyclin B1 were found to be significantly decreased in Groups I and III. A decrease in the immunohistochemical localization of these proteins was also observed in spermatogenic cells. The mRNA expressions of apoptotic factors such as Bcl-2, Bax, caspase-3 and caspase-9 were found to be increased in Groups I and III. A decrease in CDC2 kinase activity was also seen in these groups. Increased apoptosis was observed in Group I and Group III animals by terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling assay indicating oxidative-stress-mediated DNA damage. These findings suggest the effect of Se-induced oxidative stress on the cell cycle regulators and apoptotic activity of germ cells, thus providing new dimensions to molecular mechanisms underlying male infertility.
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PMID:Dietary selenium variation-induced oxidative stress modulates CDC2/cyclin B1 expression and apoptosis of germ cells in mice testis. 1732 Mar 65

In vivo application of histone deacetylase (HDAC) inhibitor trichostatin-A (TSA) in mice results in male infertility. To get more insight into the mechanisms underlying this phenomenon, we performed a genome-wide expression analysis and investigated HDAC activity and degree of histone H3 and H4 acetylation in murine testes after TSA treatment. A significant decrease in HDAC activity and a weak increase in histone acetylation could be demonstrated at 2.5, 5.0, and 7.5 hours after TSA application. Gene expression analysis revealed 507 significantly regulated genes. Transcripts expressed in the somatic cells of the testis (Sertoli, Leydig, peritubular cells, and testis macrophages) or extratubular matrix were regulated as early as 2.5 hours after TSA application, whereas very few meiosis-specific genes were modulated after TSA treatment. In addition, members of the p53-noxa-caspase-3 proapoptotic pathway were regulated early. Applying in-situ hybridization, caspase-3-mRNA was found only in apoptotic spermatocytes, whereas TRP53/p53- and PMAIP1/noxa-mRNA could be demonstrated in spermatogonia and spermatocytes. Our data suggest that TSA impaired male meiosis, possibly through an indirect mechanism implicating somatic cells of the testis.
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PMID:In vivo application of histone deacetylase inhibitor trichostatin-a impairs murine male meiosis. 1804 49

Apoptosis plays an essential role in normal spermatogenesis, but deregulations of this biological process, which is closely associated with male infertility, have been found. Whereas calcium homeostasis is a key regulator of cell survival, sustained elevation of intracellular calcium plays a role in apoptosis. The aim of this research was to determine the role of two different calcium mobilizing agents, hydrogen peroxide (H(2)O(2)) and the physiological agonist progesterone, on the apoptosis process of human ejaculated spermatozoa. Translocation of membrane phosphatidylserine was examined with an annexin V binding assay, DNA damage was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL assay) and caspase-3 activity was assessed using a fluorometric assay. After incubation of spermatozoa for 1 h with either 10 microM H(2)O(2) or 20 microM of progesterone, there was a significant increase in both caspase-3 activity and the percentage of annexin V-positive cells. Similarly, the TUNEL results were significantly higher 1 h after incubation with either 10 microM H(2)O(2) or 20 microM of progesterone. In fact, progesterone-treated cells showed a three-fold increase (from 17.6 to 52.9%) of TUNEL-positive cells compared to untreated cells, while H(2)O(2)-treated cells exhibited a two-fold increase (from 17.6 to 37.9%). In sum, our results suggest that spermatozoa treated with calcium mobilizing agents, such as H(2)O(2) and progesterone, seem to undergo an apoptosis process that is dependent on caspase-3 activation.
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PMID:Relationship between caspase activity and apoptotic markers in human sperm in response to hydrogen peroxide and progesterone. 1973 95

Maintaining the integrity of sperm DNA is vital to reproduction and male fertility. Sperm contain a number of molecules and pathways for the repair of base excision, base mismatches and DNA strand breaks. The presence of Poly (ADP-ribose) polymerase (PARP), a DNA repair enzyme, and its homologues has recently been shown in male germ cells, specifically during stage VII of spermatogenesis. High PARP expression has been reported in mature spermatozoa and in proven fertile men. Whenever there are strand breaks in sperm DNA due to oxidative stress, chromatin remodeling or cell death, PARP is activated. However, the cleavage of PARP by caspase-3 inactivates it and inhibits PARP's DNA-repairing abilities. Therefore, cleaved PARP (cPARP) may be considered a marker of apoptosis. The presence of higher levels of cPARP in sperm of infertile men adds a new proof for the correlation between apoptosis and male infertility. This review describes the possible biological significance of PARP in mammalian cells with the focus on male reproduction. The review elaborates on the role played by PARP during spermatogenesis, sperm maturation in ejaculated spermatozoa and the potential role of PARP as new marker of sperm damage. PARP could provide new strategies to preserve fertility in cancer patients subjected to genotoxic stresses and may be a key to better male reproductive health.
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PMID:Potential biological role of poly (ADP-ribose) polymerase (PARP) in male gametes. 1996 17

Varicocele-associated apoptosis has been recognised as a cause of male infertility. Thus, we assessed the expression of somatic apoptosis-related proteins (the typical protein-dependent apoptosis markers) in ejaculated sperm plasma from both patients with varicocele and normal donors. We evaluated the relationships between certain apoptosis-related proteins and normal semen quality. Semen samples were obtained from 25 patients with varicocele and from 10 normal fertile controls. These samples were compared using computer-assisted semen analysis for motion parameters and manual analysis for morphology, and were also assayed for apoptosis-related protein activation including caspase-3, poly-ACP-ribose polymerase (PARP), the Bcl-2 family (Bcl-2, Bak) and p53 by means of immunoblot analysis. PARP, Bak and p53 were expressed substantially more in the sperm cells of the varicocele group when compared with the normal group (P < 0.05). The expression of caspase-3 and Bcl-2 did not appear to differ between these two study groups. An increased expression of PARP, Bak and p53 for varicocele-afflicted individuals indicated an increased participation by these agents in the regulating of apoptosis in the ejaculated semen from patients with varicocele, suggesting that certain protein-development apoptotic mechanisms might originate in the cytoplasmic droplet or within mitochondria of spermatocytes and then might function within the nucleus of the cell.
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PMID:Effects of varicocele upon the expression of apoptosis-related proteins. 2062 44

Detection of activated caspases of spermatozoa could be helpful to evaluate male infertility. Although western blot is validated as a highly specific method to detect the proteins extracted from cells, the ability of this technique to detect activated sperm caspases in human semen may be limited. Indeed, round cells, which potentially contain some activated caspases, may be present in semen and interfere with the detection of activated sperm caspases. Moreover, it is necessary to evaluate the minimum amount of spermatozoa necessary to optimise the detection of activated caspases in semen samples. Our results showed that interference due to round cells contained in semen with activated caspase-3 requires separation of spermatozoa by density migration. This sperm preparation selects a mature sperm population that does not reflect the whole sperm population, and in infertile men with oligoasthenoteratozoospermia, the amount of spermatozoa thus selected is usually low. Moreover, the western blot technique's low detection sensitivity and the low level of caspase enzyme activity in human spermatozoa for activated caspase-3, -8 and -9 mean that large quantities of spermatozoa are needed to detect the expression of the activated caspases. These limitations prevent this method being used for routine analysis in clinical practice.
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PMID:The limits for detection of activated caspases of spermatozoa by western blot in human semen. 2229 3

Male infertility is a frequent medical condition, compromising approximately one in twenty men, with infections of the reproductive tract constituting a major etiological factor. Bacterial epididymo-orchitis results in acute inflammation most often caused by ascending canalicular infections from the urethra via the continuous male excurrent ductal system. Uropathogenic Escherichia coli (UPEC) represent a relevant pathogen in urogenital tract infections. To explore how bacteria can cause damage and cell loss and thus impair fertility, an in vivo epididymo-orchitis model was employed in rats by injecting UPEC strain CFT073 into the vas deference in close proximity to the epididymis. Seven days post infection bacteria were found predominantly in the testicular interstitial space. UPEC infection resulted in severe impairment of spermatogenesis by germ cell loss, damage of testicular somatic cells, a decrease in sperm numbers and a significant increase in TUNEL (+) cells. Activation of caspase-8 (extrinsic apoptotic pathway), caspase-3/-6 (intrinsic apoptotic pathway), caspase-1 (pyroptosis pathway) and the presence of 180 bp DNA fragments, all of which serve as indicators of the classical apoptotic pathway, were not observed in infected testis. Notably, electron microscopical examination revealed degenerative features of Sertoli cells (SC) in UPEC infected testis. Furthermore, the passive release of high mobility group protein B1 (HMGB1), as an indication of necrosis, was observed in vivo in infected testis. Thus, necrosis appears to be the dominant cell death pathway in UPEC infected testis. Substantial necrotic changes seen in Sertoli cells will contribute to impaired spermatogenesis by loss of function in supporting the dependent germ cells.
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PMID:Necrosis is the dominant cell death pathway in uropathogenic Escherichia coli elicited epididymo-orchitis and is responsible for damage of rat testis. 2330 Oct 2

Male infertility caused by testicular damage is one of the complications of diabetes mellitus. The calcium-sensing receptor (CaSR) is expressed in testicular tissues and plays a pivotal role in calcium homeostasis by activating cellular signaling pathways, but its role in testicular damage induced by diabetes remains unclear. A diabetic model was established by a single intraperitoneal injection of streptozotocin (STZ, 40 mg kg-1 ) in Wistar rats. Animals then received GdCl 3 (an agonist of CaSR, 8.67 mg kg-1 ), NPS-2390 (an antagonist of CaSR, 0.20 g kg-1 ), or a combination of both 2 months after STZ injection. Diabetic rats had significantly lower testes weights and serum levels of testosterone compared to healthy rats, indicating testicular damage and dysfunction in STZ-induced diabetic rats. Compared with healthy controls, the testicular tissues of diabetic rats overexpressed the CaSR protein and had higher levels of malondialdehyde (MDA), lower superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity, and higher numbers of apoptotic germ cells. The testicular tissues from diabetic rats also expressed lower levels of Bcl-2 and higher levels of Bax and cleaved caspase-3 in addition to higher phosphorylation rates of c-Jun NH 2 -terminal protein kinase (JNK), p38, and extracellular signaling-regulated kinase (ERK) 1/2. The above parameters could be further increased or aggravated by the administration of GdCl 3 , but could be attenuated by injection of NPS-2390. In conclusion, the present results indicate that CaSR activation participates in diabetes-induced testicular damage, implying CaSR may be a potential target for protective strategies against diabetes-induced testicular damage and could help to prevent infertility in diabetic men.
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PMID:The calcium-sensing receptor participates in testicular damage in streptozotocin-induced diabetic rats. 2638 85


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