Exploring the Role of Neuropeptide PACAP in Cytoskeletal Function Using Spectroscopic Methods.

The behavior and presence of actin-regulating proteins are characteristic of various clinical diseases. Changes in these proteins significantly impact the cytoskeletal and regenerative processes underlying pathological changes. Pituitary adenylate cyclase-activating polypeptide (PACAP), a cytoprotective neuropeptide abundant in the nervous system and endocrine organs, plays a key role in neuron differentiation and migration by influencing actin. This study aims to elucidate the role of PACAP as an actin-regulating polypeptide, its effect on actin filament formation, and the underlying regulatory mechanisms. We examined PACAP27, PACAP38, and PACAP6-38, measuring their binding to actin monomers via fluorescence spectroscopy and steady-state anisotropy. Functional polymerization tests were used to track changes in fluorescent intensity over time. Unlike PACAP27, PACAP38 and PACAP6-38 significantly reduced the fluorescence emission of Alexa488-labeled actin monomers and increased their anisotropy, showing nearly identical dissociation equilibrium constants. PACAP27 showed weak binding to globular actin (G-actin), while PACAP38 and PACAP6-38 exhibited robust interactions. PACAP27 did not affect actin polymerization, but PACAP38 and PACAP6-38 accelerated actin incorporation kinetics. Fluorescence quenching experiments confirmed structural changes upon PACAP binding; however, all studied PACAP fragments exhibited the same effect. Our findings indicate that PACAP38 and PACAP6-38 strongly bind to G-actin and significantly influence actin polymerization. Further studies are needed to fully understand the biological significance of these interactions.

Assessing the Effectiveness of a Multicomponent Intervention on Hand Hygiene and Well-Being in Primary Health Care Centers and Schools Lacking Functional Water Supply in Protracted Conflict Settings: Protocol for a Cluster Randomized Controlled Trial.

BACKGROUND: Hand hygiene is crucial in health care centers and schools to avoid disease transmission. Currently, little is known about hand hygiene in such facilities in protracted conflict settings. OBJECTIVE: This protocol aims to assess the effectiveness of a multicomponent hand hygiene intervention on handwashing behavior, underlying behavioral factors, and the well-being of health care workers and students. Moreover, we report our methodology and statistical analysis plan transparently. METHODS: This is a cluster randomized controlled trial with 2 parallel arms taking place in 4 countries for 1 year. In Burkina Faso and Mali, we worked in 24 primary health care centers per country, whereas in Nigeria and Palestine, we focused on 26 primary schools per country. Facilities were eligible if they were not connected to a functioning water source but were deemed accessible to the implementation partners. Moreover, health care centers were eligible if they had a maternity ward and ≥5 employees, and schools if they had ≤7000 students studying in grades 5 to 7. We used covariate-constrained randomization to assign intervention facilities that received a hardware, management and monitoring support, and behavior change. Control facilities will receive the same or improved intervention after endline data collection. To evaluate the intervention, at baseline and endline, we used a self-reported survey, structured handwashing observations, and hand-rinse samples. At follow-up, hand-rinse samples were dropped. Starting from the intervention implementation, we collected longitudinal data on hygiene-related health conditions and absenteeism. We also collected qualitative data with focus group discussions and interviews. Data were analyzed descriptively and with random effect regression models with the random effect at a cluster level. The primary outcome for health centers is the handwashing rate, defined as the number of times health care workers performed good handwashing practice with soap or alcohol-based handrub at one of the World Health Organization 5 moments for hand hygiene, divided by the number of moments for hand hygiene that presented themselves during the patient interaction within an hour of observation. For schools, the primary outcome is the number of students who washed their hands before eating. RESULTS: The baseline data collection across all countries lasted from February to June 2023. We collected data from 135 and 174 health care workers in Burkina Faso and Mali, respectively. In Nigeria, we collected data from 1300 students and in Palestine from 1127 students. The endline data collection began in February 2024. CONCLUSIONS: This is one of the first studies investigating hand hygiene in primary health care centers and schools in protracted conflict settings. With our strong study design, we expect to support local policy makers and humanitarian organizations in developing sustainable agendas for hygiene promotion. TRIAL REGISTRATION: ClinicalTrials.gov NCT05946980 (Burkina Faso and Mali); https://www.clinicaltrials.gov/study/NCT05946980 and NCT05964478 (Nigeria and Palestine); https://www.clinicaltrials.gov/study/NCT05964478. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/52959.

Diagnostic and Prognostic Value of PACAP in Multiple Myeloma.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a multifunctional neuropeptide with well-known anti-inflammatory, antioxidant, antitumor, and immunomodulatory effects. PACAP regulates the production of various proinflammatory factors and may influence the complex cytokine network of the bone marrow microenvironment altered by plasma cells, affecting the progression of multiple myeloma (MM) and the development of end-organ damage. The aim of our study was to investigate the changes in PACAP-38 levels in patients with MM to explore its value as a potential biomarker in this disease. We compared the plasma PACAP-38 levels of MM patients with healthy individuals by ELISA method and examined its relationship with various MM-related clinical and laboratory parameters. Lower PACAP-38 levels were measured in MM patients compared with the healthy controls, however, this difference vanished if the patient achieved any response better than partial response. In addition, lower peptide levels were found in elderly patients. Significantly higher PACAP-38 levels were seen in patients with lower stage, lower plasma cell infiltration in bone marrow, lower markers of tumor burden in serum, lower total urinary and Bence-Jones protein levels, and in patients after lenalidomide therapy. Higher PACAP-38 levels in newly diagnosed MM patients predicted longer survival and a higher probability of complete response to treatment. Our findings confirm the hypothesis that PACAP plays an important role in the pathomechanism of MM. Furthermore, our results suggest that PACAP might be used as a valuable, non-invasive, complementary biomarker in diagnosis, and may be utilized for prognosis prediction and response monitoring.

Role of endocrine PACAP in age-related diseases.

Pituitary adenylate cyclase activating polypeptide (PACAP) is a conserved neuropeptide, which confers diverse anti-aging endocrine and paracrine/autocrine effects, including anti-apoptotic, anti-inflammatory and antioxidant action. The results of the in vivo and in vitro experiments show that increasing emphasis is being placed on the diagnostic/prognostic biomarker potential of this neuropeptide in a wide array of age-related diseases. After the initial findings regarding the presence and alteration of PACAP in different body fluids in physiological processes, an increasing number of studies have focused on the changes of its levels in various pathological conditions associated with advanced aging. Until 2016 - when the results of previous human studies were reviewed - a vast majority of the studies had dealt with age-related neurological diseases, like cerebrovascular and neurodegenerative diseases, multiple sclerosis, as well as some other common diseases in elderly such as migraine, traumatic brain injury and post-traumatic stress disorder, chronic hepatitis and nephrotic syndrome. The aim of this review is to summarize the old and the new results and highlight those 'classical' and emerging clinical fields in which PACAP may become subject to further investigation as a diagnostic and/or prognostic biomarker in age-related diseases.

PACAP-38 and PAC1 Receptor Alterations in Plasma and Cardiac Tissue Samples of Heart Failure Patients.

Pituitary adenylate cyclase activating polypeptide-38 (PACAP-38) is a multifunctional neuropeptide, which may play a role in cardioprotection. However, little is known about the presence of PACAP-38 in heart failure (HF) patients. The aim of our study was to measure the alterations of PACAP-38 like immunoreactivity (LI) in acute (n = 13) and chronic HF (n = 33) and to examine potential correlations between PACAP-38 and HF predictors (cytokines, NT-proBNP). Tissue PACAP-38 LI and PAC1 receptor levels were also investigated in heart tissue samples of patients with HF. Significantly higher plasma PACAP-38 LI was detected in patients with acute HF, while in chronic HF patients, a lower level of immunoreactivity was observed compared to healthy controls (n = 13). Strong negative correlation was identified between plasma PACAP-38 and NT-proBNP levels in chronic HF, as opposed to the positive connection seen in the acute HF group. Plasma IL-1 ß, IL-2 and IL-4 levels were significantly lower in chronic HF, and IL-10 was significantly higher in patients with acute HF. PACAP-38 levels of myocardial tissues were lower in all end-stage HF patients and lower PAC1 receptor levels were detected in the primary dilated cardiomyopathy group compared to the controls. We conclude that PACAP-38 and PAC1 expression correlates with some biomarkers of acute and chronic HF; therefore, further studies are necessary to explore whether PACAP could be a suitable prognostic biomarker in HF patients.

Examination of pituitary adenylate cyclase-activating polypeptide in Parkinson's disease focusing on correlations with motor symptoms.

The neuroprotective effects of pituitary adenylate cyclase-activating polypeptide (PACAP) have been shown in numerous in vitro and in vivo models of Parkinson's disease (PD) supporting the theory that PACAP could have an important role in the pathomechanism of the disorder affecting mostly older patients. Earlier studies found changes in PACAP levels in neurological disorders; therefore, the aim of our study was to examine PACAP in plasma samples of PD patients. Peptide levels were measured with ELISA and correlated with clinical parameters, age, stage of the disorder based on the Hoehn and Yahr (HY) scale, subtype of the disease, treatment, and specific scores measuring motor and non-motor symptoms, such as movement disorder society-unified Parkinson's disease rating scale (MDS-UPDRS), Epworth sleepiness scale (ESS), Parkinson's disease sleep scale (PDSS-2), and Beck depression inventory (BDI). Our results showed significantly decreased PACAP levels in PD patients without deep brain stimulation (DBS) therapy and in akinetic-rigid subtype; additionally we also observed a further decrease in the HY stage 3 and 4. Elevated PACAP levels were found in patients with DBS. There were no significant correlations between PACAP level with MDS-UPDRS, type of pharmacological treatment, PDSS-2 sleepiness, or depression (BDI) scales, but we found increased PACAP level in patients with more severe sleepiness problems based on the ESS scale. Based on these results, we suggest that following the alterations of PACAP with other frequently used clinical biomarkers in PD patients might improve strategic planning of further therapeutic interventions and help to provide a clearer prognosis regarding the future perspective of the disease.

Protective Effects of PACAP in a Rat Model of Diabetic Neuropathy.

Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide with a widespread occurrence and diverse effects. PACAP has well-documented neuro- and cytoprotective effects, proven in numerous studies. Among others, PACAP is protective in models of diabetes-associated diseases, such as diabetic nephropathy and retinopathy. As the neuropeptide has strong neurotrophic and neuroprotective actions, we aimed at investigating the effects of PACAP in a rat model of streptozotocin-induced diabetic neuropathy, another common complication of diabetes. Rats were treated with PACAP1-38 every second day for 8 weeks starting simultaneously with the streptozotocin injection. Nerve fiber morphology was examined with electron microscopy, chronic neuronal activation in pain processing centers was studied with FosB immunohistochemistry, and functionality was assessed by determining the mechanical nociceptive threshold. PACAP treatment did not alter body weight or blood glucose levels during the 8-week observation period. However, PACAP attenuated the mechanical hyperalgesia, compared to vehicle-treated diabetic animals, and it markedly reduced the morphological signs characteristic for neuropathy: axon-myelin separation, mitochondrial fission, unmyelinated fiber atrophy, and basement membrane thickening of endoneurial vessels. Furthermore, PACAP attenuated the increase in FosB immunoreactivity in the dorsal spinal horn and periaqueductal grey matter. Our results show that PACAP is a promising therapeutic agent in diabetes-associated complications, including diabetic neuropathy.

Changes of pituitary adenylate cyclase activating polypeptide (PACAP) level in polytrauma patients in the early post-traumatic period.

In polytrauma patients who survive the primary insult, the imbalance between the pro- and anti-inflammatory processes seems to be responsible for life-threatening complications such as sepsis or multiple organ dysfunction syndrome. Measurement of C-reactive protein (CRP) and procalcitonin (PCT) is a standard way for differentiating between infectious (bacterial) and non-infectious inflammation. Monitoring of immune cell functions, like leukocyte anti-sedimentation rate (LAR) can also be useful to diagnose infectious complications. Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide with well-known immunomodulatory and anti-inflammatory effects. The aim of our study was to determine the changes of PACAP38 levels in polytrauma patients in the early post-traumatic period in intensive care unit and analyse possible correlation of its level with conventional (CRP, PCT) and unconventional (LAR) laboratory parameters. Twenty polytrauma patients were enrolled. Blood samples were taken daily for five days. We observed significant correlation between PACAP38 and CRP levels on day 4 and 5 as well as between PACAP38 and LAR levels all of the days. This could be due to the anti-inflammatory and cytoprotective functions of PACAP38 as part of an endogenous response to the trauma induced systemic inflammatory response syndrome. These significant correlations could have clinical importance in monitoring the dynamic balance of pro- and anti-inflammatory processes in case of polytraumatic patients.

PACAP-38 in Acute ST-Segment Elevation Myocardial Infarction in Humans and Pigs: A Translational Study.

Acute myocardial infarction (MI) is one of the most common causes of death worldwide. Pituitary adenylate cyclase activating polypeptide (PACAP) is a cardioprotective neuropeptide expressing its receptors in the cardiovascular system. The aim of our study was to examine tissue PACAP-38 in a translational porcine MI model and plasma PACAP-38 levels in patients with ST-segment elevation myocardial infarction (STEMI). Significantly lower PACAP-38 levels were detected in the non-ischemic region of the left ventricle (LV) in MI heart compared to the ischemic region of MI-LV and also to the Sham-operated LV in porcine MI model. In STEMI patients, plasma PACAP-38 level was significantly higher before percutaneous coronary intervention (PCI) compared to controls, and decreased after PCI. Significant negative correlation was found between plasma PACAP-38 and troponin levels. Furthermore, a significant effect was revealed between plasma PACAP-38, hypertension and HbA1c levels. This was the first study showing significant changes in cardiac tissue PACAP levels in a porcine MI model and plasma PACAP levels in STEMI patients. These results suggest that PACAP, due to its cardioprotective effects, may play a regulatory role in MI and could be a potential biomarker or drug target in MI.

Physical Training Inhibits the Fibrosis Formation in Alzheimer's Disease Kidney Influencing the TGFß Signaling Pathways.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative illness, with several peripheral pathological signs such as accumulation of amyloid-ß (Aß) plaques in the kidney. Alterations of transforming growth factor ß (TGFß) signaling in the kidney can induce fibrosis, thus disturbing the elimination of Aß. OBJECTIVE: A protective role of increased physical activity has been proven in AD and in kidney fibrosis, but it is not clear whether TGFß signalization is involved in this effect. METHODS: The effects of long-term training on fibrosis were investigated in the kidneys of mice representing a model of AD (B6C3-Tg(APPswe,PSEN1dE9)85Dbo/J) by comparing wild type and AD organs. Alterations of canonical and non-canonical TGFß signaling pathways were followed with PCR, western blot, and immunohistochemistry. RESULTS: Accumulation of collagen type I and interstitial fibrosis were reduced in kidneys of AD mice after long-term training. AD induced the activation of canonical and non-canonical TGFß pathways in non-trained mice, while expression levels of signal molecules of both TGFß pathways became normalized in trained AD mice. Decreased amounts of phosphoproteins with molecular weight corresponding to that of tau and the cleaved C-terminal of AßPP were detected upon exercising, along with a significant increase of PP2A catalytic subunit expression. CONCLUSION: Our data suggest that physical training has beneficial effects on fibrosis formation in kidneys of AD mice and TGFß signaling plays a role in this phenomenon.

Alterations of Nigral Dopamine Levels in Parkinson's Disease after Environmental Enrichment and PACAP Treatment in Aging Rats.

The neuroprotective effects of environmental enrichment and PACAP (pituitary adenylate cyclase-activating polypeptide) are well-described in Parkinson's disease. The aim of our study is to investigate the beneficial effects of these factors in aging parkinsonian rats. Newborn Wistar rats were divided into standard and enriched groups according to their environmental conditions. Standard animals were raised under regular conditions. During the first five postnatal weeks, enriched pups were placed in larger cages with different objects. Aging animals received (1) saline, (2) 6-hydroxidopamine (6-OHDA), or (3) 6-OHDA + PACAP injections into the left substantia nigra (s.n.). On the seventh postoperative day, the left and right s.n. were collected. The s.n. of young and aging unoperated animals were also examined in our experiment. We determined the dopamine (DA) levels by the HPLC-MS technique, while the sandwich ELISA method was used to measure the Parkinson disease protein 7 (PARK7) protein levels. In healthy animals, we found an age-related decrease of DA levels. In aging parkinsonian-enriched rats, the operation did not result in a significant DA loss. PACAP treatment could prevent the DA loss in both the standard and enriched groups. All injured PACAP-treated rats showed remarkably higher protective PARK7 levels. The protective effect of PACAP correlated with the increase of the DA and PARK7 levels.

Lack of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Disturbs Callus Formation.

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.

Student views of interprofessional education facilitator competencies: A cross-sectional study.

Research attention has been paid to providing evidence on undergraduate/pre-licensure health sciences students' interprofessional education competency requirements, placements, and attainment. Although interprofessional facilitator training has been identified as critical to interprofessional learner outcomes, scant research has examined student perceptions of valued facilitator competencies. This short report investigates students' views of important attributes for interprofessional facilitation using a cross-sectional observation-survey design. A survey was conducted in a pre-licensure sample of n = 343 students (response rate 68%) from four health professions (nursing, midwifery, physical therapy, and occupational therapy). After completing a semester-long interprofessional education course, students completed a survey vis-à-vis rating the importance of interprofessional facilitator competency with regard to 25 abilities, 12 teacher profiles, and 10 characteristics. Taken together, results indicate the need for a multifaceted view of interprofessional facilitator competencies. Our findings will inform training targeted to specific facilitator competencies, as needed for optimizing the delivery of interprofessional education.

Pituitary Adenylate Cyclase-Activating Polypeptide Alleviates Intestinal, Extra-Intestinal and Systemic Inflammatory Responses during Acute Campylobacter jejuni-induced Enterocolitis in Mice.

Human Campylobacter jejuni infections are emerging, and constitute a significant health burden worldwide. The ubiquitously expressed pituitary adenylate cyclase-activating polypeptide (PACAP) is well-known for its cell-protective and immunomodulatory effects. In our actual intervention study, we used an acute campylobacteriosis model and assessed the potential disease-alleviating effects of exogenous PACAP. Therefore, secondary abiotic IL-10-/- mice were perorally infected with C. jejuni and treated with synthetic PACAP38 intraperitoneally from day 2 until day 5 post-infection. Whereas PACAP did not interfere with the gastrointestinal colonization of the pathogen, mice from the PACAP group exhibited less severe clinical signs of C. jejuni-induced disease, as compared to mock controls, which were paralleled by alleviated apoptotic, but enhanced cell proliferative responses in colonic epithelia on day 6 post-infection. Furthermore, PACAP dampened the accumulation of macrophages and monocytes, but enhanced regulatory T cell responses in the colon, which were accompanied by less IFN-γ secretion in intestinal compartments in PACAP versus mock-treated mice. Remarkably, the inflammation-dampening properties of PACAP could also be observed in extra-intestinal organs, and strikingly, even the systemic circulation on day 6 post-infection. For the first time, we provide evidence that synthetic PACAP might be a promising candidate to combat acute campylobacteriosis and post-infectious sequelae.

Physical Activity Protects the Pathological Alterations of Alzheimer's Disease Kidneys via the Activation of PACAP and BMP Signaling Pathways.

Alzheimer's disease (AD) is a neurodegenerative disorder with typical amyloid beta (Aß) aggregations. Elimination of the Aß precursors via the kidneys makes the organ a potential factor in the systemic degeneration leading to AD. Pituitary adenylate cyclase-activating polypeptide (PACAP) exerts neuroprotective effects in AD and plays a protective role in kidney pathologies. Increased physical activity is preventive of the formation of AD, but its detailed mechanism and possible connections with PACAP have not been clarified. In the kidneys of AD mice, the effects of physical activity were investigated by comparing wild-type and AD organs. Aß plaque formation was reduced in AD kidneys after increased training (TAD). Mechanotransduction elevated PACAP receptor expression in TAD mice and normalized the protein kinase A (PKA)-mediated pathways. BMP4/BMPR1 elevation activated Smad1 expression and normalized collagen type IV in TAD animals. In conclusion, our data suggest that elevated physical activity can prevent the AD-induced pathological changes in the kidneys via, at least in part, the activation of PACAP-BMP signaling crosstalk.

Alzheimer's Disease Mouse as a Model of Testis Degeneration.

Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide with protective functions in the central nervous system and various peripheral organs. PACAP has the highest expression level in the testes, among the peripheral organs, and has a positive regulative role in spermatogenesis and in sperm motility. In the present study, we explored testicular degenerative alterations in a mouse model of Alzheimer's disease (AD) (B6C3-Tg(APPswe,PSEN1dE9)85Dbo/J) and demonstrated changes in PACAP-regulated signaling pathways. In addition, the effects of increased physical activity of AD (trained AD (TAD)) mice on testis were also followed. Reduced cell number and decreased thickness of basement membrane were detected in AD samples. These changes were compensated by physical activity. Expression of PACAP receptors and canonical signaling elements such as PKA, P-PKA, PP2A significantly decreased in AD mice, and altered Sox transcription factor expression was also detected. Via this signaling mechanism, physical activity compensated the negative effects of AD on the expression of type IV collagen. Our findings suggest that the testes of AD mice can be a good model of testis degeneration. Moreover, it can be an appropriate organ to follow the effects of various interventions such as physical activity on tissue regeneration and signaling alterations.

Investigation of pituitary adenylate cyclase activating polypeptide (PACAP) in human amniotic fluid samples.

Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide acting as a hormone, a neuromodulator, a neurotransmitter, a trophic factor and is involved in a variety of developmental and regenerative processes. PACAP is present in several human tissues and biological fluids. In many pathological conditions, changes in PACAP levels have been described to reflect disease progression, therefore PACAP has diagnostic value as a potential biomarker. Since PACAP has been shown to play an important role in reproductive physiology and development, it was of interest to examine whether this neuropeptide occurs in the human amniotic fluid. Amniotic fluid samples were collected between the 15-19th weeks of gestation from volunteering pregnant women undergoing amniocentesis as a prenatal diagnostic tool due to maternal age. Pathological cases were excluded after prenatal karyotype analysis. PACAP-like immunoreactivity was measured by radioimmunoassay and could be detected in all samples. The present study provides evidence for the presence of PACAP in human amniotic fluid, but determination of the exact physiological or pathological significance awaits further investigation.

Protective Effects of PACAP in Peripheral Organs.

Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide widely distributed in the nervous system, where it exerts strong neuroprotective effects. PACAP is also expressed in peripheral organs but its peripheral protective effects have not been summarized so far. Therefore, the aim of the present paper is to review the existing literature regarding the cytoprotective effects of PACAP in non-neuronal cell types, peripheral tissues, and organs. Among others, PACAP has widespread expression in the digestive system, where it shows protective effects in various intestinal pathologies, such as duodenal ulcer, small bowel ischemia, and intestinal inflammation. PACAP is present in both the exocrine and endocrine pancreas as well as liver where it reduces inflammation and steatosis by interfering with hepatic pathology related to obesity. It is found in several exocrine glands and also in urinary organs, where, with its protective effects being mainly published regarding renal pathologies, PACAP is protective in numerous conditions. PACAP displays anti-inflammatory effects in upper and lower airways of the respiratory system. In the skin, it is involved in the development of inflammatory pathology such as psoriasis and also has anti-allergic effects in a model of contact dermatitis. In the non-neuronal part of the visual system, PACAP showed protective effects in pathological conditions of the cornea and retinal pigment epithelial cells. The positive role of PACAP has been demonstrated on the formation and healing processes of cartilage and bone where it also prevents osteoarthritis and rheumatoid arthritis development. The protective role of PACAP was also demonstrated in the cardiovascular system in different pathological processes including hyperglycaemia-induced endothelial dysfunction and age-related vascular changes. In the heart, PACAP protects against ischemia, oxidative stress, and cardiomyopathies. PACAP is also involved in the protection against the development of pre-senile systemic amyloidosis, which is presented in various peripheral organs in PACAP-deficient mice. The studies summarized here provide strong evidence for the cytoprotective effects of the peptide. The survival-promoting effects of PACAP depend on a number of factors which are also shortly discussed in the present review.

The Neuroprotective and Biomarker Potential of PACAP in Human Traumatic Brain Injury.

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.

Possible effects of pituitary adenylate cyclase activating polypeptide (PACAP) on early embryo implantation marker HB-EGF in mouse.

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.