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Carmelo Romeo - One of the best experts on this subject based on the ideXlab platform.
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Mitogen-activated protein kinase 3/mitogen-activated protein kinase 1 activates apoptosis during testicular ischemia–reperfusion injury in a nuclear factor-κB-independent manner
European Journal of Pharmacology, 2008Co-Authors: Letteria Minutoli, Pietro Antonuccio, Alessandra Bitto, Francesca Polito, Francesco Squadrito, Vincenzo Di Stefano, Carmine Fazzari, Daniele Maisano, Carmelo RomeoAbstract:Abstract Nuclear factor kappa-B (NF-κB), mitogen-activated protein kinase3/MAPK1 and MAPK8 are involved in testicular ischemia reperfusion injury (testicular-I/R). NF-κB knock-out mice (KO) subjected to testicular-I/R have a reduced testicular damage, blunted MAPK8 activation and enhanced MAPK3/MAPK1 activity. To better understand the role of MAPK3/MAPK1 up-regulation during testicular-I/R, we investigated the effects of PD98059, an inhibitor of MAPK3/MAPK1, in KO mice during testicular-I/R. KO and wild-type (WT) animals underwent 1 h testicular ischemia followed by 24 h reperfusion or a sham testicular-I/R. Animals received either PD98059 (5 mg/kg/ip) or its vehicle. MAPK3/MAPK1, BAX, caspase-3 and -9 and TNF-α expression were assessed along with histological examination and an immunostaining for protein of apoptosis. Testicular-I/R caused a greater increase in MAPK3/MAPK1 in KO than in WT animals in both testes. KO mice had a lower expression of the apoptotic proteins and TNF-α as well as reduced histological damage compared to WT. Immunostaining confirmed the lower expression of BAX in the Leydig cells of KO mice. Administration of PD98059, abrogated MAPK3/MAPK1 expression and slightly reduced TNF-α but did not improve or reverse the histological damage in KO. PD98059 significantly reduced the histological damage in WT mice and markedly reduced the apoptotic proteins in KO and WT mice. These results suggest that testicular-I/R triggers also a pathway of organ damage involving MAPK3/MAPK1, TNF-α, BAX, caspase-3 and -9 that activates an apoptotic machinery in an NF-κB independent manner. These findings should contribute to better understand testicular torsion-induced damage.
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Mitogen-activated protein kinase 3/mitogen-activated protein kinase 1 activates apoptosis during testicular ischemia-reperfusion injury in a nuclear factor-kappaB-independent manner.
European journal of pharmacology, 2008Co-Authors: Letteria Minutoli, Pietro Antonuccio, Alessandra Bitto, Francesca Polito, Francesco Squadrito, Vincenzo Di Stefano, Piero Antonio Nicotina, Carmine Fazzari, Daniele Maisano, Carmelo RomeoAbstract:Nuclear factor kappa-B (NF-kappaB), mitogen-activated protein kinase3/MAPK1 and MAPK8 are involved in testicular ischemia reperfusion injury (testicular-I/R). NF-kappaB knock-out mice (KO) subjected to testicular-I/R have a reduced testicular damage, blunted MAPK8 activation and enhanced MAPK3/MAPK1 activity. To better understand the role of MAPK3/MAPK1 up-regulation during testicular-I/R, we investigated the effects of PD98059, an inhibitor of MAPK3/MAPK1, in KO mice during testicular-I/R. KO and wild-type (WT) animals underwent 1 h testicular ischemia followed by 24 h reperfusion or a sham testicular-I/R. Animals received either PD98059 (5 mg/kg/ip) or its vehicle. MAPK3/MAPK1, BAX, caspase-3 and -9 and TNF-alpha expression were assessed along with histological examination and an immunostaining for protein of apoptosis. Testicular-I/R caused a greater increase in MAPK3/MAPK1 in KO than in WT animals in both testes. KO mice had a lower expression of the apoptotic proteins and TNF-alpha as well as reduced histological damage compared to WT. Immunostaining confirmed the lower expression of BAX in the Leydig cells of KO mice. Administration of PD98059, abrogated MAPK3/MAPK1 expression and slightly reduced TNF-alpha but did not improve or reverse the histological damage in KO. PD98059 significantly reduced the histological damage in WT mice and markedly reduced the apoptotic proteins in KO and WT mice. These results suggest that testicular-I/R triggers also a pathway of organ damage involving MAPK3/MAPK1, TNF-alpha, BAX, caspase-3 and -9 that activates an apoptotic machinery in an NF-kappaB independent manner. These findings should contribute to better understand testicular torsion-induced damage.
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Evidence for a Role of Mitogen-Activated Protein Kinase 3/Mitogen-Activated Protein Kinase in the Development of Testicular Ischemia-Reperfusion Injury
Biology of reproduction, 2005Co-Authors: Letteria Minutoli, Pietro Antonuccio, Carmelo Romeo, Alessandra Bitto, Salvatore Arena, Francesca Polito, Domenica Altavilla, Nunzio Turiaco, Antonio CutrupiAbstract:Mitogen-activated protein kinase (MAPK) 3/MAPK1 (also known as ERK1/ERK2) plays an important role in the signal transduction pathways. To our knowledge, however, its role in the development of testicular ischemia-reperfusion injury has not yet been investigated. Therefore, we studied the pattern of MAPK3/MAPK1 activation in a experimental model of testicular ischemia-reperfusion injury. We also investigated MAPK8 to understand whether an association exists between these two MAPKs. Adult male Sprague-Dawley rats were subjected to 1 h of testicular ischemia followed by 24 h of reperfusion or to a sham testicular ischemia-reperfusion. Animals were randomized to receive PD98059, which is an inhibitor of MAPK3/MAPK1 (10 mg/kg i.p. administered immediately after detorsion), or its vehicle. The time course of MAPK3/MAPK1, MAPK8, and tumor necrosis factor (TNF; also known as TNF alpha) expression and a histological examination in both the ischemic-reperfused testis and the contralateral one were performed. In both testes, MAPK3/MAPK1 and MAPK8 expression appeared following 10 min of reperfusion and reached their highest activation after 30 min. The MAPK levels slowly decreased, and no significant expression of either kinase was observed following 2 h of reperfusion. Expression of TNF was evident after 1 h of reperfusion and reached its maximum increase after 3 h. PD98059 blunted MAPK3/MAPK1 and MAPK8, reduced TNF expression, and improved the testicular damage caused by ischemia-reperfusion injury in both testes. These data emphasize that MAPK3/MAPK1 has a role in testicular damage and that its blockade might have a future therapeutic role for the management of patients with unilateral testicular torsion.
Peter H Sugden - One of the best experts on this subject based on the ideXlab platform.
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activation of c jun n terminal kinases and p38 mitogen activated protein kinases in human heart failure secondary to ischaemic heart disease
Journal of Molecular and Cellular Cardiology, 1999Co-Authors: Stuart A Cook, Peter H Sugden, Angela ClerkAbstract:Three well-characterized mitogen-activated protein kinase (MAPK) subfamilies are expressed in rodent and rabbit hearts, and are activated by pathophysiological stimuli. We have determined and compared the expression and activation of these MAPKs in donor and failing human hearts. The amount and activation of MAPKs was assessed in samples from the left ventricles of 4 unused donor hearts and 12 explanted hearts from patients with heart failure secondary to ischaemic heart disease. Total MAPKs or dually phosphorylated (activated) MAPKs were detected by Western blotting and MAPK activities were measured by in gel kinase assays. As in rat heart, c-Jun N-terminal kinases (JNKs) were detected in human hearts as bands corresponding to 46 and 54 kDa; p38-MAPK(s) was detected as a band corresponding to approximately 40 kDa, and extracellularly regulated kinases, ERK1 and ERK2, were detected as 44- and 42-kDa bands respectively. The total amounts of 54 kDa JNK, p38-MAPK and ERK2 were similar in all samples, although 46-kDa JNK was reduced in the failing hearts. However, the mean activities of JNKs and p38-MAPK(s) were significantly higher in failing heart samples than in those from donor hearts (P<0.05). There was no significant difference in phosphorylated (activated) ERKs between the two groups. In conclusion, JNKs, p38-MAPK(s) and ERKs are expressed in the human heart and the activities of JNKs and p38-MAPK(s) were increased in heart failure secondary to ischaemic heart disease. These data indicate that JNKs and p38-MAPKs may be important in human cardiac pathology.
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stress responsive mitogen activated protein kinases c jun n terminal kinases and p38 mitogen activated protein kinases in the myocardium
Circulation Research, 1998Co-Authors: Peter H Sugden, Angela ClerkAbstract:The best-characterized subfamilies of the mitogen-activated protein kinase (MAPK) superfamily are the extracellularly responsive kinases (ERKs) and the two “stress-responsive” MAPK subfamilies, namely, the c-Jun N-terminal kinases (JNKs) and the p38-MAPKs.1 2 3 4 5 As yet, no single nomenclature has been determined, and the synonyms currently in use are summarized in Table 1⇓. The ERK cascade is the most thoroughly studied of the MAPK cascades, and it is activated principally by G protein–coupled receptor (GPCR) agonists in cardiac myocytes. We have reviewed this topic recently,6 and we will not discuss it in any depth here. The regulation of the JNK and p38-MAPK cascades in the myocardium (Figure 1⇓) forms the principal subject of this review. Figure 1. A scheme for the activation of stress-responsive MAPK cascades. Exposure of cultured cardiac myocytes and whole hearts to stresses or GPCR agonists leads to activation of the JNKs and p38-MAPKs. Cellular stresses induce reorganization of the cytoskeleton and activation of the small G proteins, Rac and Cdc42. GPCR agonists activate the small G protein, Ras, through a PKC-dependent mechanism. Ras is recognized to participate in the activation of the ERK cascade and, either directly or indirectly, may activate the stress-responsive MAPKs (JNKs and p38-MAPKs). The JNKs are activated by MKK4 and MKK7, whereas p38-MAPKs are activated by MKK3 and MKK6 (see Table 2⇓). The upstream activators (the MKKKs) of the stress-responsive MKKs have not been clearly defined but possibly include MEKKs (MAPK or ERK kinase kinases), mixed lineage kinases (MLKs), and/or p21-activated kinases (PAKs). Substrates for the stress-responsive MAPKs include transcription factors, which regulate the transcriptional changes, and MAPKAPK2, which phosphorylates Hsp25/27 and may thereby confer cytoprotection. CHOP indicates C/EBP homologous protein; MEF2C myocyte enhancer factor 2C. View this table: Table 1. Mitogen-Activated Protein Kinase (MAPK) Subfamilies An ever-increasing number of isoforms of …
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stimulation of stress regulated mitogen activated protein kinases stress activated protein kinases c jun n terminal kinases and p38 mitogen activated protein kinases in perfused rat hearts by oxidative and other stresses
Journal of Biological Chemistry, 1998Co-Authors: Angela Clerk, Stephen J Fuller, Ashour Michael, Peter H SugdenAbstract:Abstract “Stress-regulated” mitogen-activated protein kinases (SR-MAPKs) comprise the stress-activated protein kinases (SAPKs)/c-Jun N-terminal kinases (JNKs) and the p38-MAPKs. In the perfused heart, ischemia/reperfusion activates SR-MAPKs. Although the agent(s) directly responsible is unclear, reactive oxygen species are generated during ischemia/reperfusion. We have assessed the ability of oxidative stress (as exemplified by H2O2) to activate SR-MAPKs in the perfused heart and compared it with the effect of ischemia/reperfusion. H2O2 activated both SAPKs/JNKs and p38-MAPK. Maximal activation by H2O2 in both cases was observed at 0.5 mm. Whereas activation of p38-MAPK by H2O2 was comparable to that of ischemia and ischemia/reperfusion, activation of the SAPKs/JNKs was less than that of ischemia/reperfusion. As with ischemia/reperfusion, there was minimal activation of the ERK MAPK subfamily by H2O2. MAPK-activated protein kinase 2 (MAPKAPK2), a downstream substrate of p38-MAPKs, was activated by H2O2 to a similar extent as with ischemia or ischemia/reperfusion. In all instances, activation of MAPKAPK2 in perfused hearts was inhibited by SB203580, an inhibitor of p38-MAPKs. Perfusion of hearts at high aortic pressure (20 kilopascals) also activated the SR-MAPKs and MAPKAPK2. Free radical trapping agents (dimethyl sulfoxide and N-t-butyl-α-phenyl nitrone) inhibited the activation of SR-MAPKs and MAPKAPK2 by ischemia/reperfusion. These data are consistent with a role for reactive oxygen species in the activation of SR-MAPKs during ischemia/reperfusion.
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stimulation of the stress activated mitogen activated protein kinase subfamilies in perfused heart p38 rk mitogen activated protein kinases and c jun n terminal kinases are activated by ischemia reperfusion
Circulation Research, 1996Co-Authors: Marie A Bogoyevitch, Stephen J Fuller, Judith Gillespiebrown, Albert J Ketterman, Rachel Benlevy, Alan Ashworth, Christopher John Marshall, Peter H SugdenAbstract:It has recently been recognized that cellular stresses activate certain members of the mitogen-activated protein kinase (MAPK) superfamily. One role of these “stress-activated” MAPKs is to increase the transactivating activity of the transcription factors c-Jun, Elk1, and ATF2. These findings may be particularly relevant to hearts that have been exposed to pathological stresses. Using the isolated perfused rat heart, we show that global ischemia does not activate the 42- and 44-kD extracellular signal–regulated (protein) kinase (ERK) subfamily of MAPKs but rather stimulates a 38-kD activator of MAPK-activated protein kinase-2 (MAPKAPK2). This activation is maintained during reperfusion. The molecular characteristics of this protein kinase suggest that it is a member of the p38/reactivating kinase (RK) group of stress-activated MAPKs. In contrast, stress-activated MAPKs of the c-Jun N-terminal kinase (JNK/SAPKs) subfamily are not activated by ischemia alone but are activated by reperfusion following ischemia. Furthermore, transfection of ventricular myocytes with activated protein kinases (MEKK1 and SEK1) that may be involved in the upstream activation of JNK/SAPKs induces increases in myocyte size and transcriptional changes typical of the hypertrophic response. We speculate that activation of multiple parallel MAPK pathways may be important in the responses of hearts to cellular stresses.
Letteria Minutoli - One of the best experts on this subject based on the ideXlab platform.
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Mitogen-activated protein kinase 3/mitogen-activated protein kinase 1 activates apoptosis during testicular ischemia–reperfusion injury in a nuclear factor-κB-independent manner
European Journal of Pharmacology, 2008Co-Authors: Letteria Minutoli, Pietro Antonuccio, Alessandra Bitto, Francesca Polito, Francesco Squadrito, Vincenzo Di Stefano, Carmine Fazzari, Daniele Maisano, Carmelo RomeoAbstract:Abstract Nuclear factor kappa-B (NF-κB), mitogen-activated protein kinase3/MAPK1 and MAPK8 are involved in testicular ischemia reperfusion injury (testicular-I/R). NF-κB knock-out mice (KO) subjected to testicular-I/R have a reduced testicular damage, blunted MAPK8 activation and enhanced MAPK3/MAPK1 activity. To better understand the role of MAPK3/MAPK1 up-regulation during testicular-I/R, we investigated the effects of PD98059, an inhibitor of MAPK3/MAPK1, in KO mice during testicular-I/R. KO and wild-type (WT) animals underwent 1 h testicular ischemia followed by 24 h reperfusion or a sham testicular-I/R. Animals received either PD98059 (5 mg/kg/ip) or its vehicle. MAPK3/MAPK1, BAX, caspase-3 and -9 and TNF-α expression were assessed along with histological examination and an immunostaining for protein of apoptosis. Testicular-I/R caused a greater increase in MAPK3/MAPK1 in KO than in WT animals in both testes. KO mice had a lower expression of the apoptotic proteins and TNF-α as well as reduced histological damage compared to WT. Immunostaining confirmed the lower expression of BAX in the Leydig cells of KO mice. Administration of PD98059, abrogated MAPK3/MAPK1 expression and slightly reduced TNF-α but did not improve or reverse the histological damage in KO. PD98059 significantly reduced the histological damage in WT mice and markedly reduced the apoptotic proteins in KO and WT mice. These results suggest that testicular-I/R triggers also a pathway of organ damage involving MAPK3/MAPK1, TNF-α, BAX, caspase-3 and -9 that activates an apoptotic machinery in an NF-κB independent manner. These findings should contribute to better understand testicular torsion-induced damage.
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Mitogen-activated protein kinase 3/mitogen-activated protein kinase 1 activates apoptosis during testicular ischemia-reperfusion injury in a nuclear factor-kappaB-independent manner.
European journal of pharmacology, 2008Co-Authors: Letteria Minutoli, Pietro Antonuccio, Alessandra Bitto, Francesca Polito, Francesco Squadrito, Vincenzo Di Stefano, Piero Antonio Nicotina, Carmine Fazzari, Daniele Maisano, Carmelo RomeoAbstract:Nuclear factor kappa-B (NF-kappaB), mitogen-activated protein kinase3/MAPK1 and MAPK8 are involved in testicular ischemia reperfusion injury (testicular-I/R). NF-kappaB knock-out mice (KO) subjected to testicular-I/R have a reduced testicular damage, blunted MAPK8 activation and enhanced MAPK3/MAPK1 activity. To better understand the role of MAPK3/MAPK1 up-regulation during testicular-I/R, we investigated the effects of PD98059, an inhibitor of MAPK3/MAPK1, in KO mice during testicular-I/R. KO and wild-type (WT) animals underwent 1 h testicular ischemia followed by 24 h reperfusion or a sham testicular-I/R. Animals received either PD98059 (5 mg/kg/ip) or its vehicle. MAPK3/MAPK1, BAX, caspase-3 and -9 and TNF-alpha expression were assessed along with histological examination and an immunostaining for protein of apoptosis. Testicular-I/R caused a greater increase in MAPK3/MAPK1 in KO than in WT animals in both testes. KO mice had a lower expression of the apoptotic proteins and TNF-alpha as well as reduced histological damage compared to WT. Immunostaining confirmed the lower expression of BAX in the Leydig cells of KO mice. Administration of PD98059, abrogated MAPK3/MAPK1 expression and slightly reduced TNF-alpha but did not improve or reverse the histological damage in KO. PD98059 significantly reduced the histological damage in WT mice and markedly reduced the apoptotic proteins in KO and WT mice. These results suggest that testicular-I/R triggers also a pathway of organ damage involving MAPK3/MAPK1, TNF-alpha, BAX, caspase-3 and -9 that activates an apoptotic machinery in an NF-kappaB independent manner. These findings should contribute to better understand testicular torsion-induced damage.
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Evidence for a Role of Mitogen-Activated Protein Kinase 3/Mitogen-Activated Protein Kinase in the Development of Testicular Ischemia-Reperfusion Injury
Biology of reproduction, 2005Co-Authors: Letteria Minutoli, Pietro Antonuccio, Carmelo Romeo, Alessandra Bitto, Salvatore Arena, Francesca Polito, Domenica Altavilla, Nunzio Turiaco, Antonio CutrupiAbstract:Mitogen-activated protein kinase (MAPK) 3/MAPK1 (also known as ERK1/ERK2) plays an important role in the signal transduction pathways. To our knowledge, however, its role in the development of testicular ischemia-reperfusion injury has not yet been investigated. Therefore, we studied the pattern of MAPK3/MAPK1 activation in a experimental model of testicular ischemia-reperfusion injury. We also investigated MAPK8 to understand whether an association exists between these two MAPKs. Adult male Sprague-Dawley rats were subjected to 1 h of testicular ischemia followed by 24 h of reperfusion or to a sham testicular ischemia-reperfusion. Animals were randomized to receive PD98059, which is an inhibitor of MAPK3/MAPK1 (10 mg/kg i.p. administered immediately after detorsion), or its vehicle. The time course of MAPK3/MAPK1, MAPK8, and tumor necrosis factor (TNF; also known as TNF alpha) expression and a histological examination in both the ischemic-reperfused testis and the contralateral one were performed. In both testes, MAPK3/MAPK1 and MAPK8 expression appeared following 10 min of reperfusion and reached their highest activation after 30 min. The MAPK levels slowly decreased, and no significant expression of either kinase was observed following 2 h of reperfusion. Expression of TNF was evident after 1 h of reperfusion and reached its maximum increase after 3 h. PD98059 blunted MAPK3/MAPK1 and MAPK8, reduced TNF expression, and improved the testicular damage caused by ischemia-reperfusion injury in both testes. These data emphasize that MAPK3/MAPK1 has a role in testicular damage and that its blockade might have a future therapeutic role for the management of patients with unilateral testicular torsion.
Pietro Antonuccio - One of the best experts on this subject based on the ideXlab platform.
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Mitogen-activated protein kinase 3/mitogen-activated protein kinase 1 activates apoptosis during testicular ischemia–reperfusion injury in a nuclear factor-κB-independent manner
European Journal of Pharmacology, 2008Co-Authors: Letteria Minutoli, Pietro Antonuccio, Alessandra Bitto, Francesca Polito, Francesco Squadrito, Vincenzo Di Stefano, Carmine Fazzari, Daniele Maisano, Carmelo RomeoAbstract:Abstract Nuclear factor kappa-B (NF-κB), mitogen-activated protein kinase3/MAPK1 and MAPK8 are involved in testicular ischemia reperfusion injury (testicular-I/R). NF-κB knock-out mice (KO) subjected to testicular-I/R have a reduced testicular damage, blunted MAPK8 activation and enhanced MAPK3/MAPK1 activity. To better understand the role of MAPK3/MAPK1 up-regulation during testicular-I/R, we investigated the effects of PD98059, an inhibitor of MAPK3/MAPK1, in KO mice during testicular-I/R. KO and wild-type (WT) animals underwent 1 h testicular ischemia followed by 24 h reperfusion or a sham testicular-I/R. Animals received either PD98059 (5 mg/kg/ip) or its vehicle. MAPK3/MAPK1, BAX, caspase-3 and -9 and TNF-α expression were assessed along with histological examination and an immunostaining for protein of apoptosis. Testicular-I/R caused a greater increase in MAPK3/MAPK1 in KO than in WT animals in both testes. KO mice had a lower expression of the apoptotic proteins and TNF-α as well as reduced histological damage compared to WT. Immunostaining confirmed the lower expression of BAX in the Leydig cells of KO mice. Administration of PD98059, abrogated MAPK3/MAPK1 expression and slightly reduced TNF-α but did not improve or reverse the histological damage in KO. PD98059 significantly reduced the histological damage in WT mice and markedly reduced the apoptotic proteins in KO and WT mice. These results suggest that testicular-I/R triggers also a pathway of organ damage involving MAPK3/MAPK1, TNF-α, BAX, caspase-3 and -9 that activates an apoptotic machinery in an NF-κB independent manner. These findings should contribute to better understand testicular torsion-induced damage.
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Mitogen-activated protein kinase 3/mitogen-activated protein kinase 1 activates apoptosis during testicular ischemia-reperfusion injury in a nuclear factor-kappaB-independent manner.
European journal of pharmacology, 2008Co-Authors: Letteria Minutoli, Pietro Antonuccio, Alessandra Bitto, Francesca Polito, Francesco Squadrito, Vincenzo Di Stefano, Piero Antonio Nicotina, Carmine Fazzari, Daniele Maisano, Carmelo RomeoAbstract:Nuclear factor kappa-B (NF-kappaB), mitogen-activated protein kinase3/MAPK1 and MAPK8 are involved in testicular ischemia reperfusion injury (testicular-I/R). NF-kappaB knock-out mice (KO) subjected to testicular-I/R have a reduced testicular damage, blunted MAPK8 activation and enhanced MAPK3/MAPK1 activity. To better understand the role of MAPK3/MAPK1 up-regulation during testicular-I/R, we investigated the effects of PD98059, an inhibitor of MAPK3/MAPK1, in KO mice during testicular-I/R. KO and wild-type (WT) animals underwent 1 h testicular ischemia followed by 24 h reperfusion or a sham testicular-I/R. Animals received either PD98059 (5 mg/kg/ip) or its vehicle. MAPK3/MAPK1, BAX, caspase-3 and -9 and TNF-alpha expression were assessed along with histological examination and an immunostaining for protein of apoptosis. Testicular-I/R caused a greater increase in MAPK3/MAPK1 in KO than in WT animals in both testes. KO mice had a lower expression of the apoptotic proteins and TNF-alpha as well as reduced histological damage compared to WT. Immunostaining confirmed the lower expression of BAX in the Leydig cells of KO mice. Administration of PD98059, abrogated MAPK3/MAPK1 expression and slightly reduced TNF-alpha but did not improve or reverse the histological damage in KO. PD98059 significantly reduced the histological damage in WT mice and markedly reduced the apoptotic proteins in KO and WT mice. These results suggest that testicular-I/R triggers also a pathway of organ damage involving MAPK3/MAPK1, TNF-alpha, BAX, caspase-3 and -9 that activates an apoptotic machinery in an NF-kappaB independent manner. These findings should contribute to better understand testicular torsion-induced damage.
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Evidence for a Role of Mitogen-Activated Protein Kinase 3/Mitogen-Activated Protein Kinase in the Development of Testicular Ischemia-Reperfusion Injury
Biology of reproduction, 2005Co-Authors: Letteria Minutoli, Pietro Antonuccio, Carmelo Romeo, Alessandra Bitto, Salvatore Arena, Francesca Polito, Domenica Altavilla, Nunzio Turiaco, Antonio CutrupiAbstract:Mitogen-activated protein kinase (MAPK) 3/MAPK1 (also known as ERK1/ERK2) plays an important role in the signal transduction pathways. To our knowledge, however, its role in the development of testicular ischemia-reperfusion injury has not yet been investigated. Therefore, we studied the pattern of MAPK3/MAPK1 activation in a experimental model of testicular ischemia-reperfusion injury. We also investigated MAPK8 to understand whether an association exists between these two MAPKs. Adult male Sprague-Dawley rats were subjected to 1 h of testicular ischemia followed by 24 h of reperfusion or to a sham testicular ischemia-reperfusion. Animals were randomized to receive PD98059, which is an inhibitor of MAPK3/MAPK1 (10 mg/kg i.p. administered immediately after detorsion), or its vehicle. The time course of MAPK3/MAPK1, MAPK8, and tumor necrosis factor (TNF; also known as TNF alpha) expression and a histological examination in both the ischemic-reperfused testis and the contralateral one were performed. In both testes, MAPK3/MAPK1 and MAPK8 expression appeared following 10 min of reperfusion and reached their highest activation after 30 min. The MAPK levels slowly decreased, and no significant expression of either kinase was observed following 2 h of reperfusion. Expression of TNF was evident after 1 h of reperfusion and reached its maximum increase after 3 h. PD98059 blunted MAPK3/MAPK1 and MAPK8, reduced TNF expression, and improved the testicular damage caused by ischemia-reperfusion injury in both testes. These data emphasize that MAPK3/MAPK1 has a role in testicular damage and that its blockade might have a future therapeutic role for the management of patients with unilateral testicular torsion.
Francesca Polito - One of the best experts on this subject based on the ideXlab platform.
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Mitogen-activated protein kinase 3/mitogen-activated protein kinase 1 activates apoptosis during testicular ischemia–reperfusion injury in a nuclear factor-κB-independent manner
European Journal of Pharmacology, 2008Co-Authors: Letteria Minutoli, Pietro Antonuccio, Alessandra Bitto, Francesca Polito, Francesco Squadrito, Vincenzo Di Stefano, Carmine Fazzari, Daniele Maisano, Carmelo RomeoAbstract:Abstract Nuclear factor kappa-B (NF-κB), mitogen-activated protein kinase3/MAPK1 and MAPK8 are involved in testicular ischemia reperfusion injury (testicular-I/R). NF-κB knock-out mice (KO) subjected to testicular-I/R have a reduced testicular damage, blunted MAPK8 activation and enhanced MAPK3/MAPK1 activity. To better understand the role of MAPK3/MAPK1 up-regulation during testicular-I/R, we investigated the effects of PD98059, an inhibitor of MAPK3/MAPK1, in KO mice during testicular-I/R. KO and wild-type (WT) animals underwent 1 h testicular ischemia followed by 24 h reperfusion or a sham testicular-I/R. Animals received either PD98059 (5 mg/kg/ip) or its vehicle. MAPK3/MAPK1, BAX, caspase-3 and -9 and TNF-α expression were assessed along with histological examination and an immunostaining for protein of apoptosis. Testicular-I/R caused a greater increase in MAPK3/MAPK1 in KO than in WT animals in both testes. KO mice had a lower expression of the apoptotic proteins and TNF-α as well as reduced histological damage compared to WT. Immunostaining confirmed the lower expression of BAX in the Leydig cells of KO mice. Administration of PD98059, abrogated MAPK3/MAPK1 expression and slightly reduced TNF-α but did not improve or reverse the histological damage in KO. PD98059 significantly reduced the histological damage in WT mice and markedly reduced the apoptotic proteins in KO and WT mice. These results suggest that testicular-I/R triggers also a pathway of organ damage involving MAPK3/MAPK1, TNF-α, BAX, caspase-3 and -9 that activates an apoptotic machinery in an NF-κB independent manner. These findings should contribute to better understand testicular torsion-induced damage.
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Mitogen-activated protein kinase 3/mitogen-activated protein kinase 1 activates apoptosis during testicular ischemia-reperfusion injury in a nuclear factor-kappaB-independent manner.
European journal of pharmacology, 2008Co-Authors: Letteria Minutoli, Pietro Antonuccio, Alessandra Bitto, Francesca Polito, Francesco Squadrito, Vincenzo Di Stefano, Piero Antonio Nicotina, Carmine Fazzari, Daniele Maisano, Carmelo RomeoAbstract:Nuclear factor kappa-B (NF-kappaB), mitogen-activated protein kinase3/MAPK1 and MAPK8 are involved in testicular ischemia reperfusion injury (testicular-I/R). NF-kappaB knock-out mice (KO) subjected to testicular-I/R have a reduced testicular damage, blunted MAPK8 activation and enhanced MAPK3/MAPK1 activity. To better understand the role of MAPK3/MAPK1 up-regulation during testicular-I/R, we investigated the effects of PD98059, an inhibitor of MAPK3/MAPK1, in KO mice during testicular-I/R. KO and wild-type (WT) animals underwent 1 h testicular ischemia followed by 24 h reperfusion or a sham testicular-I/R. Animals received either PD98059 (5 mg/kg/ip) or its vehicle. MAPK3/MAPK1, BAX, caspase-3 and -9 and TNF-alpha expression were assessed along with histological examination and an immunostaining for protein of apoptosis. Testicular-I/R caused a greater increase in MAPK3/MAPK1 in KO than in WT animals in both testes. KO mice had a lower expression of the apoptotic proteins and TNF-alpha as well as reduced histological damage compared to WT. Immunostaining confirmed the lower expression of BAX in the Leydig cells of KO mice. Administration of PD98059, abrogated MAPK3/MAPK1 expression and slightly reduced TNF-alpha but did not improve or reverse the histological damage in KO. PD98059 significantly reduced the histological damage in WT mice and markedly reduced the apoptotic proteins in KO and WT mice. These results suggest that testicular-I/R triggers also a pathway of organ damage involving MAPK3/MAPK1, TNF-alpha, BAX, caspase-3 and -9 that activates an apoptotic machinery in an NF-kappaB independent manner. These findings should contribute to better understand testicular torsion-induced damage.
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Evidence for a Role of Mitogen-Activated Protein Kinase 3/Mitogen-Activated Protein Kinase in the Development of Testicular Ischemia-Reperfusion Injury
Biology of reproduction, 2005Co-Authors: Letteria Minutoli, Pietro Antonuccio, Carmelo Romeo, Alessandra Bitto, Salvatore Arena, Francesca Polito, Domenica Altavilla, Nunzio Turiaco, Antonio CutrupiAbstract:Mitogen-activated protein kinase (MAPK) 3/MAPK1 (also known as ERK1/ERK2) plays an important role in the signal transduction pathways. To our knowledge, however, its role in the development of testicular ischemia-reperfusion injury has not yet been investigated. Therefore, we studied the pattern of MAPK3/MAPK1 activation in a experimental model of testicular ischemia-reperfusion injury. We also investigated MAPK8 to understand whether an association exists between these two MAPKs. Adult male Sprague-Dawley rats were subjected to 1 h of testicular ischemia followed by 24 h of reperfusion or to a sham testicular ischemia-reperfusion. Animals were randomized to receive PD98059, which is an inhibitor of MAPK3/MAPK1 (10 mg/kg i.p. administered immediately after detorsion), or its vehicle. The time course of MAPK3/MAPK1, MAPK8, and tumor necrosis factor (TNF; also known as TNF alpha) expression and a histological examination in both the ischemic-reperfused testis and the contralateral one were performed. In both testes, MAPK3/MAPK1 and MAPK8 expression appeared following 10 min of reperfusion and reached their highest activation after 30 min. The MAPK levels slowly decreased, and no significant expression of either kinase was observed following 2 h of reperfusion. Expression of TNF was evident after 1 h of reperfusion and reached its maximum increase after 3 h. PD98059 blunted MAPK3/MAPK1 and MAPK8, reduced TNF expression, and improved the testicular damage caused by ischemia-reperfusion injury in both testes. These data emphasize that MAPK3/MAPK1 has a role in testicular damage and that its blockade might have a future therapeutic role for the management of patients with unilateral testicular torsion.