Pituitary adenylate cyclase-activating polypeptide (PACAP) is a widespread neuropeptide with a diverse array of biological functions. Not surprisingly, the lack of endogenous PACAP therefore results in a variety of abnormalities. One of the important effects of PACAP is its neuroprotective and general cytoprotective role. PACAP protects neurons and other tissues against ischemic, toxic, and traumatic lesions. Data obtained from PACAP-deficient mice provide evidence that endogenous PACAP also has protective functions. Mice lacking PACAP are more vulnerable to different in vitro and in vivo insults. The present review summarizes data on the increased sensitivity of PACAP-deficient mice against harmful stimuli. Mice lacking PACAP respond with a higher degree of injury in cerebral ischemia, autoimmune encephalomyelitis, and axonal lesion. Retinal ischemic and excitotoxic injuries also produce increased cell loss in PACAP-deficient mice. In peripheral organs, kidney cell cultures from PACAP-deficient mice are more sensitive to oxidative stress and in vitro hypoxia. In vivo, PACAP-deficient mice have a negative histological outcome and altered cytokine response in kidney and small intestine ischemia/reperfusion injury. Large intestinal inflammation, toxic lesion of the pancreas, and doxorubicin-induced cardiomyopathy are also more severe with a lack of endogenous PACAP. Finally, an increased inflammatory response has been described in subacute endotoxin-induced airway inflammation and in an oxazolone-induced allergic contact dermatitis model. In summary, lack of endogenous PACAP leads to higher vulnerability in a number of injuries in the nervous system and peripheral organs, supporting the hypothesis that PACAP is part of the endogenous cytoprotective machinery.

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Our results suggest that Gal-9 could be a promising noninvasive biomarker of endometriosis and a predictor of various infertility or pelvic pain-related gynecologic disorders.

Introduction There is increasing evidence that intermediate and long‐term bowel dysfunction may occur as a consequence of radical surgery for rectal deep endometriosis (DE). Typical symptoms include constipation, feeling of incomplete evacuation, clustering of stools, and urgency. This is described in the colorectal surgical literature as low anterior resection syndrome (LARS). Within this, several studies suggested that differences regarding functional outcomes could be favorable to more conservative surgical approaches, that is, excision of endometriotic tissue with preservation of the luminal structure of the rectal wall when compared with classical segmental resection techniques for DE, especially when performed for low DE. Material and methods A total of 211 patients undergoing rectal surgery for low DE (≤7 cm from the anal verge) in three different tertiary referral centers between October 2009 and December 2018 were retrospectively reviewed regarding major complications and LARS. From the 211 eligible patients, six women were excluded because of loss to follow‐up. Finally, a total number of 205 patients were enrolled for the statistical analysis; 139 with nerve‐ and vessel‐sparing segmental resection (NVSSR) and 66 operated for laparoscopic‐transanal disk excision (LTADE) were included. Gastrointestinal functional outcomes of the two procedures were compared using the validated LARS questionnaire. The median follow‐up time was 46 ± 11 months. As a secondary outcome, the surgical sequelae were examined. Results We found no statistically significant difference between the incidence of LARS (31.7% and 37.9%, respectively) among patients operated by LTADE when compared with NVSSR (P = .4). The occurrence of LARS was positively associated with the use of protective ileostomy or colostomy (P = .02). A higher rate of severe complications was observed in women undergoing LTADE (19.7%) when compared with patients with NVSSR (9.0%, P = .029). Conclusions LARS is not more frequent after NVSSR when compared with a more conservative approach such as LTADE in patients undergoing rectal surgery for low DE. To confirm our findings prospective studies are required.

The effects of pituitary adenylate cyclase activating polypeptide (PACAP) are mediated through G-protein-coupled receptors, the specific PAC1 receptor and VPAC1 and VPAC2 receptors which bind vasoactive intestinal peptide with similar affinity. Based on binding affinity studies, PACAP6-38 was discovered as a potent antagonist of PAC1 and it has been used by hundreds of studies as a PACAP antagonist. Recently, we have found that in certain cells/tissues, PACAP6-38 does not antagonize PACAP-induced effects, but surprisingly, it exerts similar actions to PACAP1-38, behaving as an agonist. In the present study, we report on the agonistic behavior of PACAP6-38 on neuropeptide release from sensory nerves of the isolated rat trachea and on the MAPK signaling pathways in cytotrophoblast cells. In isolated rat tracheae, PACAP6-38, similarly to PACAP1-38, induced significant inhibitory effects on the release of three simultaneously measured sensory neuropeptides, substance P, calcitonin gene-related peptide, and somatostatin evoked by both chemical excitation and electrical field stimulation of capsaicin-sensitive afferents. Effects of PACAP6-38 were the same as those of PACAP1-38 on MAPK signaling in human cytotrophoblast cells. Western blot analysis showed that both peptide forms stimulated ERK1/2 and JNK phosphorylation, while they both inhibited p38 MAPK phosphorylation. The most pronounced effects were observed when both peptides were present. In summary, our results show that PACAP6-38, which is a PACAP receptor antagonist in most cells/tissues, can behave as an agonist in other systems. The increasing interest in the effects of PACAP requires further studies on the pharmacological properties of the peptide and its analogues.