RESUMO
Pituitary adenylate cyclase activating polypeptide (PACAP ) is a multifunctional neuropeptide occurring in the nervous system as well as in the peripheral organs. Beneficial action of PACAP has been shown in different pathological processes. The strong protective effects of the peptide are probably due to its complex modulatory actions in antiapoptotic, anti-inflammatory and antioxidant pathways. In the kidney, PACAP is protective in models of diabetic nephropathy, myeloma kidney injury, cisplatin-, gentamycin- and cyclosporin-induced damages. Numerous studies have been published describing the protective effect of this peptide in renal ischemia/reperfusion. The present review focuses on the ischemia/reperfusion-induced kidney injury and gives a brief summary about the results published in this area.
Assuntos
Nefropatias/prevenção & controle , Rim/enzimologia , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Traumatismo por Reperfusão/enzimologia , Animais , Humanos , Nefropatias/enzimologia , Nefropatias/patologia , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/administração & dosagem , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Traumatismo por Reperfusão/patologia , Transdução de SinaisRESUMO
Authors draw attention to their own experience about the occurrence and epidemic measures of tuberculosis in two micro-regions of Hungary, Fadd and Józsefváros situated far from each other. According to data from the National Statistical Office of Hungary, tuberculosis does not belong to the most significant causes of morbidity and mortality. However, it still represents a notable factor in national healthcare and public health. Currently, tuberculosis is not an important issue to be regulated by health care decision makers or at the level of legislation. Based on their own experience, authors suggest reconsidering the possibility of epidemic measures for the prevention of tuberculosis.
Assuntos
Surtos de Doenças/prevenção & controle , Órgãos Governamentais , Programas de Rastreamento/métodos , Saúde Pública , Tuberculose Pulmonar/epidemiologia , Tuberculose Pulmonar/prevenção & controle , Adulto , Criança , Feminino , Órgãos Governamentais/normas , Órgãos Governamentais/tendências , Humanos , Hungria/epidemiologia , Incidência , Masculino , Saúde Pública/economia , Saúde Pública/legislação & jurisprudência , Saúde Pública/normas , Saúde Pública/tendências , Estudantes/estatística & dados numéricos , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/transmissãoRESUMO
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide that exerts general cytoprotective effects, including protection in different kidney disorders. The aim of our study was to investigate the ischemia/reperfusion-induced kidney injury of male and female rats to confirm the protective effects of PACAP in the kidney and to reveal possible gender differences.Male and female Wistar rats underwent unilateral renal artery clamping followed by 24-h, 48-h, or 14-day reperfusion. PACAP was administered intravenously before arterial clamping in half of the rats. Tubular damage, cytokine expression pattern, oxidative stress marker, antioxidative status and signaling pathways were evaluated using histology, immunohistology, cytokine array, PCR, and Western blot. Tubular damage was significantly less severe in the PACAP-treated male and female rats compared to controls. Results of female animals were significantly better in both treated and untreated groups. Cytokine expression, oxidative stress marker and antioxidative status confirmed the histological results. We also revealed that PACAP counteracted the decreased PKA phosphorylation, influenced the expression of BMP2 and BMP4, and increased the expression of the protein Smad1.We conclude that PACAP is protective in ischemia/reperfusion-induced kidney injury in both sexes, but females had markedly less pronounced injury after ischemia/reperfusion, possibly also involving further protective factors, the investigation of which could have future therapeutic value in treating ischemic kidney injuries.
Assuntos
Injúria Renal Aguda/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Rim/efeitos dos fármacos , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Injúria Renal Aguda/etiologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Citocinas/sangue , Feminino , Rim/irrigação sanguínea , Rim/metabolismo , Masculino , Estresse Oxidativo , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/farmacologia , Ratos , Ratos Wistar , Traumatismo por Reperfusão/complicações , Fatores Sexuais , Proteína Smad1/genética , Proteína Smad1/metabolismoRESUMO
INTRODUCTION: Peritoneal dissemination accompanied by ascites formation is common in epithelial ovarian cancer (EOC). Adhesion molecules are crucial in metastatic spread and the latter involves epithelial-mesenchymal transition (EMT). This study aimed at: (1) clarifying whether E-cadherin and ß-catenin expression and proliferative activity in metastatic ovarian cancer are inter-related; (2) Identifying possible correlations between cell adhesion molecular expression profiles, the proliferative activity and p53 expression of tumor cells and tumor grade and stage; (3) testing the cytology microarray (CMA) technique in analyzing metastasis formation. MATERIAL AND METHODS: Both tumorous and ascitic samples from 27 EOC patients were examined by using tissue microarray (TMA) and cytology microarray (CMA), respectively. CMA blocks were constructed using cores from each cell block of the ascitic specimens. Expression of E-cadherin, ß-catenin, Ki-67 and p53 was immunohistochemically detected both in TMA and CMA blocks. RESULTS: E-cadherin expression was higher in ascitic cells than in primary tumor cells (pâ¯=â¯.294). ß-catenin expression was significantly lower in ascitic cells than in primary tumor cells (pâ¯=â¯.006). Expression of Ki-67 was lower and expression of p53 was higher in primary tumors than in ascitic cells, for p53 the difference was significant (pâ¯=â¯.001). Both Ki-67 and p53 expression elevated significantly in high-grade primary tumor cells and in ascites cells (pâ¯=â¯.039, and pâ¯=â¯.004, respectively). CONCLUSION: Epithelial-mesenchymal transition- mesenchymal-epithelial transition is suggested as the best descriptive term for our IHC observations which accompany increased proliferative activity of ascitic cells. The CMA method is an adequate and reliable method for the analysis of ascitic tumor cells disseminating from ovarian malignancies.
Assuntos
Caderinas/metabolismo , Moléculas de Adesão Celular/metabolismo , Proliferação de Células/fisiologia , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Peritoneais/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Carcinoma Epitelial do Ovário , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Feminino , Humanos , Análise em Microsséries/métodos , Pessoa de Meia-Idade , Adulto JovemRESUMO
Pituitary adenylate cyclase activating polypeptide (PACAP) is a widespread neuropeptide with diverse effects in the nervous system and peripheral organs. One of the most well-studied effects of PACAP is its cytoprotective action, against different harmful stimuli in a wide variety of cells and tissues. PACAP occurs in the urinary system, from the kidney to the lower urinary tract. The present review focuses on the nephroprotective effects of PACAP and summarizes data obtained regarding the protective effects of PACAP in different models of kidney pathologies. In vitro data show that PACAP protects tubular cells against oxidative stress, myeloma light chain, cisplatin, cyclosporine-A and hypoxia. In vivo data provide evidence for its protective effects in ischemia/reperfusion, cisplatin, cyclosporine-A, myeloma kidney injury, diabetic nephropathy and gentamicin-induced kidney damage. Results accumulated on the renoprotective effects of PACAP suggest that PACAP is an emerging candidate for treatment of human kidney pathologies.
Assuntos
Nefropatias/metabolismo , Nefropatias/prevenção & controle , Rim/enzimologia , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Sistema Urinário/enzimologia , Animais , Cisplatino/farmacologia , Cisplatino/toxicidade , Ciclosporina/toxicidade , Humanos , Hipóxia/metabolismo , Isquemia/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Estresse Oxidativo/efeitos dos fármacos , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/farmacologia , Reperfusão , Sistema Urinário/efeitos dos fármacosRESUMO
Oxidative stress plays an important role in various renal and hepatic pathologies, and reduction of oxidative stress-induced processes is an important protective strategy in tissues of diverse origins against harmful stimuli. Pituitary adenylate cyclase activating polypeptide (PACAP) is a well-known cytotrophic and cytoprotective peptide. PACAP promotes cell survival in numerous cells and tissues exposed to various stimuli. Protective effects of PACAP have been shown in the kidney, but it is not known whether PACAP is protective against oxidative stress in renal cells. Little is known about the effects of PACAP in the liver. The aim of the present study was to investigate whether PACAP is protective against oxidative stress in primary rat kidney cell culture and whether PACAP has any effect on cell survival in human WRL-68 hepatocytes and HEP-G2 hepatocellular carcinoma cells subjected to oxidative stress. Cells were exposed to various concentrations of H(2)O(2) with or without PACAP co-treatment and cell viability was evaluated with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide test (MTT). We found that oxidative stress induced a significant decrease in cell viability in both cell lines. PACAP could dose-dependently increase the percentage of living cells in kidney cells, but it failed to do so in hepatocytes. Given the survival-promoting effects of PACAP against oxidative stress in rat kidney, we conducted a further experiment to determine whether PACAP influences the markers of oxidative stress in vivo. We have proven earlier that PACAP was effective in kidney ischemia/reperfusion injury in vivo. In the present study, we determined the levels of the oxidative stress marker malondialdehyde and the activity of the scavenger molecules glutathione (GSH) and superoxide dismutase (SOD) following kidney ischemia/reperfusion in rats. We found that PACAP significantly increased the level of GSH and counteracted the marked reduction of SOD activity after ischemia/reperfusion in vivo. In summary, the present study showed that while PACAP was able to significantly increase the cell survival in primary kidney cell cultures exposed to oxidative stress, possibly involving interaction with the endogenous scavenger system, it failed to influence the viability of normal or cancerous hepatocytes.
Assuntos
Morte Celular/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Rim/efeitos dos fármacos , Rim/patologia , Estresse Oxidativo/fisiologia , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/farmacologia , Animais , Biomarcadores/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Hepatócitos/citologia , Humanos , Rim/citologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide with well-known cytoprotective effects. We have reported earlier that PACAP decreases mortality and the degree of tubular atrophy in a rat model of renal ischemia/reperfusion injury. Recently, we have shown that kidney cultures isolated from PACAP deficient mice show increased susceptibility to renal oxidative stress. Based on these previous studies, we raised the question whether PACAP deficient mice display increased sensitivity to in vivo kidney ischemia/reperfusion. PACAPâ»/â» mice underwent 45 or 60 min of renal ischemia followed by 2 weeks reperfusion. Kidneys were processed for histological analysis. Sections stained with PAS-haematoxylin were graded for the following parameters: degree of tubular dilation, Bowmann's capsule dilation, lymphocyte and macrophage infiltration, thyroidization and the disappearance of the PAS-positive glycocalyx from under the brush border. In other sets of experiments, tissue cytokine expression and the level of the endogenous antioxidant superoxide dismutase (SOD) were also determined after 60 min ischemia/reperfusion. Our results show that while intact kidneys were not different between wild-type and PACAP deficient mice, marked differences were observed in the histological structures in groups that underwent ischemia/reperfusion. PACAP deficient mice had a worse histological outcome, with significantly higher histological scores for all tested parameters. Cytokine expression was also markedly different between wild-type and PACAP deficient mice. In addition, the level of SOD was significantly lower in PACAPâ»/â» animals after ischemia/reperfusion. In conclusion, the lack of endogenous PACAP leads to higher susceptibility to in vivo renal ischemia/reperfusion, suggesting that PACAP has an endogenous renoprotective effect.
Assuntos
Rim/patologia , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/deficiência , Traumatismo por Reperfusão/patologia , Animais , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Rim/metabolismo , Camundongos , Camundongos Knockout , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética , Ratos , Superóxido Dismutase/metabolismoRESUMO
Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide with highly efficient cytoprotective actions. Its neuroprotective effects are well-known, but PACAP is able to exert similar actions in non-neuronal cells. Recently, we have shown that PACAP prolongs renal ischemic time, decreases mortality, and attenuates tubular degeneration in a rat model of renal ischemia/reperfusion, but the mechanism of renoprotection is not yet known. Therefore, the aim of the present study was to obtain further insight into the renoprotective effects of PACAP by examining its direct effects of PACAP on mitochondrial permeability transition in vitro and on the expression of the anti-apoptotic Bcl-2 and cytokines/chemokines in kidney tissues following 45 and 60 min renal ischemia and reperfusion in vivo. We found that PACAP did not have any direct effect on mitochondrial permeability transition. Cytokine array revealed that the expression of a few cytokines/chemokines was strongly increased after ischemia/reperfusion, which was ameliorated by PACAP treatment. Furthermore, in rats subjected to renal ischemia, PACAP treatment counteracted the ischemia/reperfusion-induced decrease of the anti-apoptotic Bcl-2, both after 45 and 60 min ischemia, as analyzed by Western blot. In summary, we showed that PACAP could attenuate tissue injury involving both anti-inflammatory and anti-apoptotic effects, but not directly acting on mitochondrial permeability transition.