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1.
Int J Mol Sci ; 21(3)2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-32012887

RESUMO

Traumatic brain injury remains a growing public health concern and represents the greatest contributor to death and disability globally among all trauma-related injuries. There are limited clinical data regarding biomarkers in the diagnosis and outcome prediction of TBI. The lack of real effective treatment for recovery calls for research of TBI to be shifted into the area of prevention, treatment of secondary brain injury and neurorehabilitation. The neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) has been reported to act as a hormone, a neuromodulator, a neurotransmitter and a trophic factor, and has been implicated in a variety of developmental and regenerative processes. The importance of PACAP in neuronal regeneration lies in the upregulation of endogenous PACAP and its receptors and the protective effect of exogenous PACAP after different central nervous system injury. The aim of this minireview is to summarize both the therapeutic and biomarker potential of the neuropeptide PACAP, as a novel possible target molecule presently being investigated in several human conditions including TBI, and with encouraging results in animal models of TBI.

2.
Reprod Biol ; 20(1): 9-13, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31964586

RESUMO

Pituitary adenylate cyclase activating polypeptide (PACAP) was originally isolated as a hypothalamic neuropeptide stimulating adenylate cyclase activity. Besides its neuroprotective effects, numerous data proved its role in reproductive processes. However, there are limited data on its role in preimplantation embryo development and implantation. Our aim was to analyse the mRNA expression of Adcyap1 (coding region of PACAP) and Hbegf [coding region of HB-EGF (Heparin-binding EGF-like growth factor)] in embryos and pregnant uterus to investigate the possible correlation between them. Eight-week-old BDF1 mice were superovulated and subsequently mated overnight or left in their cage after hCG treatment. Day4 embryos were flushed from mated females. After morphological analysis, Adcyap1 and Hbegf gene expression of embryos and uterine tissues was assessed with qPCR. Our results showed significantly higher Adcyap1 and Hbegf mRNA levels in females producing embryos compared to non-mated ones. Robust elevation of Adcyap1 and slight elevation of Hbegf were detected in females with blastocyst embryos compared with non-blastocysts. We found low rate of Hbegf mRNA expression in uncompacted embryos, whereas morulae and blastocysts expressed high amounts of Hbegf. However, we did not find detectable Adcyap1 mRNA in embryos. Strong correlation was found between uterine tissue and embryonic Hbegf levels, slight correlation between uterine Adcyap1 and Hbegf levels. Uterine tissue Adcyap1 and embryonic Hbegf showed no correlation. In summary, our present data show, for the first time, the correlation between PACAP and HB-EGF mRNA expression suggesting that PACAP might play a role during the peri-implantation period of early mouse embryo development.

3.
Am J Reprod Immunol ; 83(3): e13212, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31758623

RESUMO

PROBLEM: Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide having several regulatory functions in the nervous system and in peripheral organs including those of the reproductive system. PACAP-deficient male mice have several morphological, biochemical, behavioral defects and show disturbed signaling in spermatogenesis affecting fertility in PACAP KO mice. Reproductive functions such as fertility, mating, and maternal behaviors have been widely investigated, but no immune analyses are available regarding the testicular immune-privileged environment in male PACAP-deficient mice. METHOD OF STUDY: We performed detailed immunophenotyping of testicular immune cells and investigated the expression of TIM-3 and PD-1 Immune checkpoint molecules of immune cells together with the detection of galectin-9 and perforin. We investigated the percentage of numerous immune cell populations in the testis of wild-type and PACAP-deficient mice. RESULTS: We demonstrated a significant increase in the frequency of testicular CD8+ T cells together with the decrease in Treg cell number obtained from PACAP KO mice compared with wild-type mice. Investigating Immune checkpoint receptors, only PD-1 showed a significantly decreased expression in CD8+ T cells in PACAP KO mice compared with wild-type suggesting an impaired PD-1/PD-L1 pathway. Regarding TIM-3 expression, we did not find any significant difference between the investigated groups. CONCLUSION: We hypothesize that these local changes may result in an immune activation with disturbed testicular immunoregulation in PACAP KO mice; however, determining the exact function requires further investigations. Our data further support the view that besides a systemic immune tolerance, localized active immunosuppression is involved in the regulation of testicular immune privilege.

4.
J Mol Neurosci ; 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31808034

RESUMO

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a naturally secreted signaling peptide and has important regulatory roles in the differentiation of the central nervous system and its absence results in disorders in femur development. PACAP has an important function in prevention of oxidative stress or mechanical stress in chondrogenesis but little is known about its function in bone regeneration. A new callus formation model was set to investigate its role in bone remodeling. Fracturing was 5 mm distal from the proximal articular surface of the tibia and the depth was 0.5 mm. Reproducibility of callus formation was investigated with CT 3, 7, and 21 days after the operation. Absence of PACAP did not alter the alkaline phosphatase (ALP) activation in PACAP KO healing process. In developing callus, the expression of collagen type I increased in wild-type (WT) and PACAP KO mice decreased to the end of healing process. Expression of the elements of BMP signaling was disturbed in the callus formation of PACAP KO mice, as bone morphogenic protein 4 (BMP4) and 6 showed an early reduction in bone regeneration. However, elevated Smad1 expression was demonstrated in PACAP KO mice. Our results indicate that PACAP KO mice show various signs of disturbed bone healing and suggest PACAP compensatory and fine tuning effects in proper bone regeneration.

5.
Oncol Lett ; 18(6): 5725-5730, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31788045

RESUMO

Pancreatic carcinoma is one of the most malignant diseases and is associated with a poor survival rate. Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide that acts on three different G protein-coupled receptors: the specific PAC1 and the VPAC1/2 that also bind vasoactive intestinal peptide. PACAP is widely distributed in the body and has diverse physiological effects. Among other things, it acts as a trophic factor and influences proliferation and differentiation of several different cells both under normal circumstances and tumourous transformation. Changes of PACAP and its receptors have been shown in various tumour types. However, it is not known whether PACAP and its specific receptor are altered in pancreatic cancer. Perioperative data of patients with pancreas carcinoma was investigated over a five-year period. Histological results showed Grade 2 or Grade 3 adenocarcinoma in most cases. PACAP and PAC1 receptor expression were investigated by immunohistochemistry. Staining intensity of PAC1 receptor was strong in normal tissues both in the exocrine and endocrine parts of the pancreas, the receptor staining was markedly weaker in the adenocarcinoma. PACAP immunostaining was weak in the exocrine part and very strong in the islets and nerve elements in non-tumourous tissues. The PACAP immunostaining almost disappeared in the adenocarcinoma samples. Based on these findings a decrease or lack of the PAC1 receptor/PACAP signalling might have an influence on tumour growth and/or differentiation.

6.
Geroscience ; 41(6): 775-793, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31655957

RESUMO

Pituitary adenylate cyclase activating polypeptide (PACAP) is an evolutionarly conserved neuropeptide which is produced by various neuronal and non-neuronal cells, including cartilage and bone cells. PACAP has trophic functions in tissue development, and it also plays a role in cellular and tissue aging. PACAP takes part in the regulation of chondrogenesis, which prevents insufficient cartilage formation caused by oxidative and mechanical stress. PACAP knockout (KO) mice have been shown to display early aging signs affecting several organs. In the present work, we investigated articular cartilage of knee joints in young and aged wild-type (WT) and PACAP KO mice. A significant increase in the thickness of articular cartilage was detected in aged PACAP gene-deficient mice. Amongst PACAP receptors, dominantly PAC1 receptor was expressed in WT knee joints and a remarkable decrease was found in aged PACAP KO mice. Expression of PKA-regulated transcription factors, Sox5, Sox9 and CREB, decreased both in young and aged gene deficient mice, while Sox6, collagen type II and aggrecan expressions were elevated in young but were reduced in aged PACAP KO animals. Increased expression of hyaluronan (HA) synthases and HA-binding proteins was detected parallel with an elevated presence of HA in aged PACAP KO mice. Expression of bone related collagens (I and X) was augmented in young and aged animals. These results suggest that loss of PACAP signaling results in dysregulation of cartilage matrix composition and may transform articular cartilage in a way that it becomes more prone to degenerate.

7.
Int J Mol Sci ; 20(19)2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31591326

RESUMO

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic neuropeptide with a widespread distribution throughout the entire body including the urinary system. PACAP exerts protective actions in different injury models related to several organ systems. Its protective effect is mainly based on its antiapoptotic, anti-inflammatory and antioxidant effects. The present review aims to summarize the effects of PACAP in pathologies associated with inflammation and oxidative stress-induced damage in the kidney. Both in vitro and in vivo data are available proving its protective actions against oxidative stress, hypoxia, renal ischemia/reperfusion, diabetic nephropathy, myeloma kidney injury, amyloidosis and different types of drug-induced nephropathies. Data showing the nephroprotection by PACAP emphasize the potential of PACAP's therapeutic use in various renal pathologies.


Assuntos
Anti-Inflamatórios/administração & dosagem , Rim/lesões , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/administração & dosagem , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Sobrevivência Celular , Citocinas/metabolismo , Humanos , Rim/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/farmacologia
8.
Sci Rep ; 9(1): 14598, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601840

RESUMO

Pituitary adenylate cyclase activating polypeptide (PACAP) is a regulatory and cytoprotective neuropeptide, its deficiency implies accelerated aging in mice. It is present in the auditory system having antiapoptotic effects. Expression of Ca2+-binding proteins and its PAC1 receptor differs in the inner ear of PACAP-deficient (KO) and wild-type (WT) mice. Our aim was to elucidate the functional role of PACAP in the auditory system. Auditory brainstem response (ABR) tests found higher hearing thresholds in KO mice at click and low frequency burst stimuli. Hearing impairment at higher frequencies showed as reduced ABR wave amplitudes and latencies in KO animals. Increase in neuronal activity, demonstrated by c-Fos immunolabeling, was lower in KO mice after noise exposure in the ventral and dorsal cochlear nuclei. Noise induced neuronal activation was similar in further relay nuclei of the auditory pathway of WT and KO mice. Based on the similar inflammatory and angiogenic protein profile data from cochlear duct lysates, neither inflammation nor disturbed angiogenesis, as potential pathological components in sensorineural hearing losses, seem to be involved in the pathomechanism of the presented functional and morphological changes in PACAP KO mice. The hearing impairment is probably concomitant with the markedly accelerated aging processes in these animals.

9.
Orv Hetil ; 160(32): 1270-1278, 2019 Aug.
Artigo em Húngaro | MEDLINE | ID: mdl-31387373

RESUMO

Introduction: During recent decades, the perinatal mortality of extremely low-birth weight infants has decreased. An important task is to recognize complications of prematurity. Aim: We made an attempt to explore the relationship between complications of prematurity and neonatal hyperglycemia. Method: From 1 January 2014 to 31 December 2017, 188 infants with birth weight below 1000 g were admitted. For each infant, the frequencies of hyperglycemia (blood glucose >8.5 mmol/l), retinopathy of prematurity, intraventricular hemorrhage, and bronchopulmonary dysplasia were determined. Animal studies were performed in Sprague Dawley rats. Hyperglycemia was achieved by intraperitoneal injection of streptozotocin (100 mg/kg). On the 7th day of life, aorta sections were prepared and stained with hematoxylin eosin. Wall thickness was measured using QCapture Pro 7 image analysis software. Results: The mean ± SD gestational age and birth weight were 27.1 ± 2.2 weeks and 814.9 ± 151.9 g; 33 infants (17.5%) died. Hyperglycemia was confirmed in 62 cases (32.9%), and insulin treatment was given to 43 infants (22.8%). The gestational age and birth weight of the hyperglycemic infants were significantly lower (p<0.001), the incidence of severe retinopathy (p = 0.012) and the mortality of insulin-treated patients were higher (p = 0.02) than in normoglycemic infants. Among survivors (n = 155), we found by logistic regression analysis that hyperglycemia was a risk factor for severe retinopathy (p<0.001). In the rat model, neonatal hyperglycemia caused significant thickening of the aortic wall. Conclusion: Our studies indicate that hyperglycemia is common in extremely low birth-weight infants. Monitoring of these infants for retinopathy of prematurity, kidney dysfunction, and hypertension is recommended. Orv Hetil. 2019; 160(32): 1270-1278.


Assuntos
Diabetes Mellitus Experimental , Hiperglicemia , Recém-Nascido de Peso Extremamente Baixo ao Nascer , Doenças do Prematuro , Retinopatia da Prematuridade/etiologia , Animais , Peso ao Nascer , Displasia Broncopulmonar/epidemiologia , Hemorragia Cerebral Intraventricular/epidemiologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Feminino , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Recém-Nascido de muito Baixo Peso , Gravidez , Ratos , Ratos Sprague-Dawley , Retinopatia da Prematuridade/epidemiologia
10.
Ann N Y Acad Sci ; 1455(1): 160-172, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31317557

RESUMO

The purpose of this study was to determine whether pituitary adenylate cyclase activating polypeptide (PACAP) could influence the neovascularization processes in hyperosmotic and oxidative stress in retinal pigment epithelial cells. Hyperosmotic conditions and oxidative stress were induced by 200 mM sucrose and 250 µM hydrogen peroxide (H2 O2 ), respectively. Morphology and elasticity of adult retinal pigment epithelial (ARPE-19) cells were measured by atomic force microscopy, while the investigation of junctional molecules, such as occludin and ZO-1, was carried out using immunofluorescence. For cell viability measurement, the MTT test was used. The effect of PACAP on the key angiogenic factors, such as vascular endothelial growth factor, angiogenin, and endothelin-1, was measured by an angiogenesis array and flow cytometry. Hyperosmotic stress-induced reorganization of the cytoskeleton and impairment of the junctions decreased cell viability and upregulated several angiogenic factors. In oxidative stress, we found that opening of the junctions decreased viability and upregulated the expression of angiogenic factors. PACAP was shown to be protective in both conditions. Retinal pigment epithelium cells play an important role in several diseases, such as diabetic retinopathy and macular edema. Therefore, protecting retinal pigment epithelial (RPE) cells with PACAP could be a novel and potential treatment in these diseases.

11.
Artigo em Inglês | MEDLINE | ID: mdl-31192159

RESUMO

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) is an endogenous neuropeptide with distinct functions including the regulation of inflammatory processes. PACAP is able to modify the immune response by directly regulating macrophages and monocytes inhibiting the production of inflammatory cytokines, chemokines and free radicals. Here, we analyzed the effect of exogenous PACAP on peripheral immune cell subsets upon acute infection with the parasite Toxoplasma gondii (T. gondii). PACAP administration was followed by diminished innate immune cell recruitment to the peritoneal cavity of T. gondii-infected mice. PACAP did not directly interfere with parasite replication, instead, indirectly reduced parasite burden in mononuclear cell populations by enhancing their phagocytic capacity. Although proinflammatory cytokine levels were attenuated in the periphery upon PACAP treatment, interleukin (IL)-10 and Transforming growth factor beta (TGF-ß) remained stable. While PACAP modulated VPAC1 and VPAC2 receptors in immune cells upon binding, it also increased their expression of brain-derived neurotrophic factor (BDNF). In addition, the expression of p75 neurotrophin receptor (p75NTR) on Ly6Chi inflammatory monocytes was diminished upon PACAP administration. Our findings highlight the immunomodulatory effect of PACAP on peripheral immune cell subsets during acute Toxoplasmosis, providing new insights about host-pathogen interaction and the effects of neuropeptides during inflammation.


Assuntos
Interações Hospedeiro-Patógeno/imunologia , Imunomodulação , Neuropeptídeos/imunologia , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/administração & dosagem , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/imunologia , Toxoplasmose/imunologia , Animais , Antígenos Ly , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Quimiocinas/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Imunidade Inata , Inflamação , Interleucina-10 , Macrófagos , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Crescimento Neural , Receptores Tipo II de Peptídeo Intestinal Vasoativo , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo , Toxoplasma , Regulação para Cima
12.
Geroscience ; 41(5): 619-630, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31144244

RESUMO

Age-related impairment of angiogenesis likely has a critical role in cerebromicrovascular rarefaction and development of vascular cognitive impairment and dementia (VCID) in the elderly. Recently, we demonstrated that aging is associated with NAD+ depletion in the vasculature and that administration of NAD+ precursors exerts potent anti-aging vascular effects, rescuing endothelium-mediated vasodilation in the cerebral circulation and improving cerebral blood supply. The present study was designed to elucidate how treatment with nicotinamide mononucleotide (NMN), a key NAD+ intermediate, impacts age-related impairment of endothelial angiogenic processes. Using cerebromicrovascular endothelial cells (CMVECs) isolated from young and aged F344xBN rats, we demonstrated that compared with young cells, aged CMVECs exhibit impaired proliferation, cellular migration (measured by a wound-healing assay using electric cell-substrate impedance sensing [ECIS] technology), impaired ability to form capillary-like structures, and increased oxidative stress. NMN treatment in aged CMVECs significantly improved angiogenic processes and attenuated H2O2 production. We also found that pre-treatment with EX-527, a pharmacological inhibitor of SIRT1, prevented NMN-mediated restoration of angiogenic processes in aged CMVECs. Collectively, we find that normal cellular NAD+ levels are essential for normal endothelial angiogenic processes, suggesting that age-related cellular NAD+ depletion and consequential SIRT1 dysregulation may be a potentially reversible mechanism underlying impaired angiogenesis and cerebromicrovascular rarefaction in aging. We recommend that pro-angiogenic effects of NAD+ boosters should be considered in both preclinical and clinical studies.

13.
Invest Ophthalmol Vis Sci ; 60(5): 1478-1490, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30973576

RESUMO

Purpose: In the eye, chronic hypoxia/reoxygenation (H/R) contributes to the development of a number of ocular disorders. H/R induces the production of reactive oxygen species (ROS), leading to poly(ADP-ribose) polymerase-1 (PARP1) activation that promotes inflammation, cell death, and disease progression. Here, we analyzed the protective effects of the PARP1 inhibitor olaparib in H/R-induced retina injury and investigated the signaling mechanisms involved. Methods: A rat retinal H/R model was used to detect histologic and biochemical changes in the retina. Results: H/R induced reductions in the thickness of most retinal layers, which were prevented by olaparib. Furthermore, H/R caused increased levels of Akt and glycogen synthase kinase-3ß phosphorylation, which were further increased by olaparib, contributing to retina protection. By contrast, H/R-induced c-Jun N-terminal kinase and p38 mitogen-activated protein kinases (MAPK) phosphorylation and activation were reduced by olaparib, via mitogen-activated protein kinase phosphatase 1 (MKP-1) expression. In addition, H/R-induced hypoxia-inducible factor 1α (HIF1α) levels were decreased by olaparib, which possibly contributed to reduced VEGF expression. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression was slightly increased by H/R and was further activated by olaparib. Nuclear factor-κB (NFκB) was also activated by H/R through phosphorylation (Ser536) and acetylation (Lys310) of the p65 subunit, although this was significantly reduced by olaparib. Conclusions: Olaparib reduced H/R-induced degenerative changes in retinal morphology. The protective mechanisms of olaparib most probably involved Nrf2 activation and ROS reduction, as well as normalization of HIF1α and related VEGF expression. In addition, olaparib reduced inflammation by NFκB dephosphorylation/inactivation, possibly via the PARP1 inhibition-MKP-1 activation-p38 MAPK inhibition pathway. PARP inhibitors represent potential therapeutics in H/R-induced retinal disease.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Doenças Retinianas/prevenção & controle , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Doença Crônica , Citocinas/metabolismo , Modelos Animais de Doenças , Técnica Indireta de Fluorescência para Anticorpo , Hipóxia/complicações , Immunoblotting , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Estresse Oxidativo , Oxigênio/toxicidade , Fosforilação , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/metabolismo , Doenças Retinianas/metabolismo
14.
Front Immunol ; 10: 554, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30967875

RESUMO

The neuropeptide Pituitary adenylate cyclase-activating polypeptide (PACAP) is well-known for its important functions in immunity and inflammation. Data regarding anti-inflammatory properties of PACAP in the intestinal tract are limited, however. In our present preclinical intervention study we addressed whether PACAP treatment could alleviate experimental subacute ileitis mimicking human gut microbiota conditions. Therefore, secondary abioitic mice were subjected to human fecal microbiota transplantation (FMT) and perorally infected with low-dose Toxoplasma gondii to induce subacute ileitis on day 0. From day 3 until day 8 post-infection, mice were either treated with synthetic PACAP38 or placebo. At day 9 post-infection, placebo, but not PACAP treated mice exhibited overt macroscopic sequelae of intestinal immunopathology. PACAP treatment further resulted in less distinct apoptotic responses in ileal and colonic epithelia that were accompanied by lower T cell numbers in the mucosa and lamina propria and less secretion of pro-inflammatory cytokines in intestinal ex vivo biopsies. Notably, ileitis-associated gut microbiota shifts were less distinct in PACAP as compared to placebo treated mice. Inflammation-ameliorating effects of PACAP were not restricted to the intestines, but could also be observed in extra-intestinal including systemic compartments as indicated by lower apoptotic cell counts and less pro-inflammatory cytokine secretion in liver and lungs taken from PACAP treated as compared to placebo control mice, which also held true for markedly lower serum TNF and IL-6 concentrations in the former as compared to the latter. Our preclinical intervention study provides strong evidence that synthetic PACAP alleviates subacute ileitis and extra-intestinal including systemic sequelae of T cell-driven immunopathology. These findings further support PACAP as a novel treatment option for intestinal inflammation including inflammatory bowel diseases (IBD).

15.
Int Breastfeed J ; 14: 9, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30792750

RESUMO

Background: Breast milk provides nutrition for infants and also contains a variety of bioactive factors that influence the development of the newborn. Human milk is a complex biological fluid that can be separated into different layers (water phase and lipid phase with its component water and lipid fractions). It can affect the developing human body along the whole length of the gastrointestinal tract, and through the circulation, its factors may reach every organ. Methods: In the present study, we analyzed milk samples collected monthly for 6 months from 16 mothers from the 4th week postpartum between 2014 and 2016 in Baranya County, Hungary. The 96 samples provided us information about the fluctuation of certain bioactive factors during the first 6 months of lactation. We investigated with Luminex technology the concentrations of several cytokines (CD40, Flt-3L), chemokines (MCP-1, RANTES, GRO, MIP-1ß, MDC, eotaxin, fractalkine), and epidermal growth factor (EGF). Paired t-tests and one-way ANOVA followed by Bonferroni post-hoc tests were used to compare the data. Results: We detected the presence of each bioactive factor in every layer of the milk samples during the first 6 months of breastfeeding in widespread concentration ranges. In the case of GRO, MIP-1ß, MDC, Flt-3L, fractalkine, and eotaxin, the concentrations were constant during the first 6 months of lactation. The water phase of human milk contained higher factor concentrations compared to both fractions of the lipid phase for most factors (except eotaxin and MIP-1ß). The concentrations of CD40, EGF, MCP-1, and RANTES in the first 3 months were significantly different compared to the values detected between 4th and 6th months. In the water phase, the level of MCP-1 was significantly decreased, while all of the other factors increased during the 4th through 6th months. We found significantly higher EGF, GRO, and RANTES levels in the water fraction compared to the lipid fraction of the lipid phase. Conclusions: The novel findings of this investigation were the presence of Flt-3L and MDC in all layers of breast milk, and nearly all bioactive factors in the lipid phase. Due to their widespread physiological effects these factors may have an essential role in organogenesis.

16.
PLoS One ; 14(1): e0211433, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30682157

RESUMO

BACKGROUND: PACAP and VIP are closely related neuropeptides with wide distribution and potent effect in the vasculature. We previously reported vasomotor activity in peripheral vasculature of male wild type (WT) and PACAP-deficient (KO) mice. However, female vascular responses are still unexplored. We hypothesized that PACAP-like activity is maintained in female PACAP KO mice and the mechanism through which it is regulated differs from that of male PACAP KO animals. METHODS: We investigated the vasomotor effects of VIP and PACAP isoforms and their selective blockers in WT and PACAP KO female mice in carotid and femoral arteries. The expression and level of different PACAP receptors in the vessels were measured by RT-PCR and Western blot. RESULTS: In both carotid and femoral arteries of WT mice, PACAP1-38, PACAP1-27 or VIP induced relaxation, without pronounced differences between them. Reduced relaxation was recorded only in the carotid arteries of KO mice as compared to their WT controls. The specific VPAC1R antagonist completely blocked the PACAP/VIP-induced relaxation in both arteries of all mice, while PAC1R antagonist affected relaxation only in their femoral arteries. CONCLUSION: In female WT mice, VPAC1 receptors appear to play a dominant role in PACAP-induced vasorelaxation both in carotid and in femoral arteries. In the PACAP KO group PAC1R activation exerts vasorelaxation in the femoral arteries but in carotid arteries there is no significant effect of the activation of this receptor. In the background of this regional difference, decreased PAC1R and increased VPAC1R availability in the carotid arteries was found.


Assuntos
Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/metabolismo , Vasodilatação , Animais , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/fisiologia , Feminino , Artéria Femoral/efeitos dos fármacos , Artéria Femoral/fisiologia , Proteínas de Insetos/farmacologia , Camundongos , Camundongos Knockout , Nitroprussiato/farmacologia , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/deficiência , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/farmacologia , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/antagonistas & inibidores , Peptídeo Intestinal Vasoativo/farmacologia , Vasodilatação/efeitos dos fármacos
17.
Neurochem Int ; 124: 238-244, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30682380

RESUMO

Alcohol addiction is a worldwide concern as its detrimental effects go far beyond the addicted individual and can affect the entire family as well as the community. Considerable effort is being expended in understanding the neurobiological basis of such addiction in hope of developing effective prevention and/or intervention strategies. In addition, organ damage and neurotoxicological effects of alcohol are intensely investigated. Pharmacological approaches, so far, have only provided partial success in prevention or treatment of alcohol use disorder (AUD) including the neurotoxicological consequences of heavy drinking. Pituitary adenylate cyclase-activating polypeptide (PACAP) is an endogenous 38 amino-acid neuropeptide with demonstrated protection against neuronal injury, trauma as well as various endogenous and exogenous toxic agents including alcohol. In this mini-review, following a brief presentation of alcohol addiction and its neurotoxicity, the potential of PACAP as a therapeutic intervention in toxicological consequences of this devastating disorder is discussed.


Assuntos
Intoxicação Alcoólica/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Etanol/toxicidade , Fármacos Neuroprotetores/uso terapêutico , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/uso terapêutico , Intoxicação Alcoólica/metabolismo , Intoxicação Alcoólica/patologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Etanol/administração & dosagem , Humanos , Fármacos Neuroprotetores/farmacologia , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/farmacologia , Vasodilatadores/farmacologia , Vasodilatadores/uso terapêutico
18.
Int J Mol Sci ; 20(1)2019 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-30621194

RESUMO

Pituitary adenylate cyclase activating polypeptide (PACAP) is an endogenous neuropeptide also secreted by non-neural cells, including chondrocytes. PACAP signaling is involved in the regulation of chondrogenesis, but little is known about its connection to matrix turnover during cartilage formation and under cellular stress in developing cartilage. We found that the expression and activity of hyaluronidases (Hyals), matrix metalloproteinases (MMP), and aggrecanase were permanent during the course of chondrogenesis in primary chicken micromass cell cultures, although protein levels changed daily, along with moderate and relatively constant enzymatic activity. Next, we investigated whether PACAP influences matrix destructing enzyme activity during oxidative and mechanical stress in chondrogenic cells. Exogenous PACAP lowered Hyals and aggrecanase expression and activity during cellular stress. Expression and activation of the majority of cartilage matrix specific MMPs such as MMP1, MMP7, MMP8, and MMP13, were also decreased by PACAP addition upon oxidative and mechanical stress, while the activity of MMP9 seemed not to be influenced by the neuropeptide. These results suggest that application of PACAP can help to preserve the integrity of the newly synthetized cartilage matrix via signaling mechanisms, which ultimately inhibit the activity of matrix destroying enzymes under cellular stress. It implies the prospect that application of PACAP can ameliorate articular cartilage destruction in joint diseases.


Assuntos
Proteínas Reguladoras de Apoptose/farmacologia , Condrócitos/efeitos dos fármacos , Estresse Oxidativo , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/farmacologia , Estresse Mecânico , Animais , Proteínas Reguladoras de Apoptose/administração & dosagem , Cartilagem/efeitos dos fármacos , Cartilagem/metabolismo , Técnicas de Cultura de Células , Embrião de Galinha , Condrócitos/metabolismo , Endopeptidases/metabolismo , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Hialuronoglucosaminidase/metabolismo , Peróxido de Hidrogênio/farmacologia , Metaloproteinases da Matriz/metabolismo , Oxidantes/farmacologia
19.
J Mol Neurosci ; 68(3): 368-376, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29353438

RESUMO

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic and multifunctional neuropeptide having neurotrophic, neuroprotective, and general cytoprotective actions in a variety of tissues based on its anti-apoptotic, anti-inflammatory, and antioxidant effects. Several studies have demonstrated its cardioprotective effects in vitro and in various animal models. However, few data are available on the presence of PACAP in human cardiac tissues and its role in the pathomechanism and progression of different cardiac disorders, particularly heart failure. Earlier, our research group has shown PAC1 receptor immunoreactivity in human heart tissue samples and we have found significantly elevated PACAP27- and PACAP38-like immunoreactivity in ischemic cardiac samples compared to valvular abnormalities with radioimmunoassay. In the last few years, numerous studies examined the presence and the changes of PACAP levels in different human tissue samples and biological fluids to show alterations in different physiological and pathological conditions. Therefore, the aim of the present study was to measure the alterations of blood PACAP levels in chronic heart failure caused by primary dilated cardiomyopathy or ischemic cardiomyopathy and to examine the possible relationship between serum levels of PACAP, N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and systolic left ventricular function, the most reliable biomarkers of heart failure. In the group of mild heart failure patients, a significant strong negative correlation was detected. Furthermore, in moderate heart failure, we found a significant moderate negative correlation between PACAP and NT-proBNP levels only in ischemic subgroup. Positive correlation was found between serum PACAP level and ejection fraction only in patients with heart failure due to ischemic cardiomyopathy but not in patients with primary dilated cardiomyopathy. In summary, remarkable differences were observed between the ischemic and non-ischemic heart failure suggesting that PACAP might play an important role in the pathomechanism and progression of ischemic heart failure and it might be a potential biomarker of cardiac diseases in the future.


Assuntos
Cardiomiopatia Dilatada/sangue , Insuficiência Cardíaca/sangue , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/sangue , Idoso , Biomarcadores/sangue , Cardiomiopatia Dilatada/complicações , Cardiomiopatia Dilatada/fisiopatologia , Feminino , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Precursores de Proteínas/sangue , Função Ventricular Esquerda
20.
J Mol Neurosci ; 68(3): 408-419, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30443839

RESUMO

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
Lesão 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 , Lesão 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/metabolismo
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