Endometriosis is a gynecological condition that is associated with chronic pelvic inflammation, pain, and infertility. Although substantial evidence supports that immunological alterations contribute to its pathogenesis and we previously posed a pivotal role of Galectin-9 (Gal-9) in this disorder, the involvement of the TIM-3/Gal-9 pathway in the development of endometriosis-associated immunological abnormalities is not yet known. In the present study, multicolor flow cytometry was used to compare the immunophenotype and cell surface expression of TIM-3 and Gal-9 molecules on peripheral blood (PB) and peritoneal fluid (PF) lymphocytes of women with and without endometriosis. We found an altered distribution of different lymphocyte subpopulations, a markedly decreased TIM-3 labeling on all T and NK subsets and a significantly increased Gal-9 positivity on peripheral CD4+ T and Treg cells of the affected cohort. Furthermore, a significantly increased TIM-3 expression on CD4+T-cells and elevated Gal-9 labeling on all T and NK subsets was also revealed in the PF of the examined patients. In conclusion, our results suggest a persistent activation and disturbed TIM-3/Gal-9-dependent regulatory function in endometriosis, which may be involved in the impaired immune surveillance mechanisms, promotes the survival of ectopic lesions, and aids the evolution of reproductive failures in endometriosis.

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.

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.

Background: The importance of immune checkpoint molecules is well known in tumor and transplantation immunology; however, much less information is available regarding human pregnancy. Despite the significant amount of information about the TIGIT and CD226 immune checkpoint receptors in immune therapies, very little research has been conducted to study the possible role of these surface molecules and their ligands (CD112 and CD155) during the three trimesters of pregnancy. Methods: From peripheral blood, immune cell subpopulations were studied, and the surface expression of immune checkpoint molecules was analyzed by flow cytometry. Soluble immune checkpoint molecule levels were measured by ELISA. Results: Notable changes were observed regarding the percentage of monocyte subpopulation and the expression of CD226 receptor by CD4⁺ T and NKT cells. Elevated granzyme B content by the intermediate and non-classical monocytes was assessed as pregnancy proceeded. Furthermore, we revealed an important relationship between the CD226 surface expression by NKT cells and the serum CD226 level in the third trimester of pregnancy. Conclusions: Our results confirm the importance of immune checkpoint molecules in immunoregulation during pregnancy. CD226 seems to be a significant regulator, especially in the case of CD4⁺ T and NKT cells, contributing to the maternal immune tolerance in the late phase of pregnancy.

Background: Medication-related osteonecrosis of the jaw (MRONJ) is a common adverse event following antiresorptive treatment, leading to chronic inflammation and exposed, necrotic bone surfaces in the jawbone. There is an increasing recognition of the role of compositional changes in the colonizing members of the oral microbiota implicated in triggering and/or maintaining MRONJ. The aim of our study was to characterize the culturable and non-culturable microbiota—with particular focus on Actinomyces spp. and Actinomyces-like organisms (ALOs)—from surgically removed bone samples of MRONJ patients and healthy control subjects. Methods: n = 35 patients (median age: 70 years) in various stages of MRONJ, with a history of receiving oral or intravenous antiresorptive treatment were included in the study. The controls (n = 35; median age: 35 years) consisted of otherwise healthy individuals undergoing tooth extraction. Traditional, quantitative, aerobic, and anaerobic culture, and Actinomyces-specific PCR was performed for all bone samples from patients and controls, while microbiome analyses—based on 16S rRNA sequencing—were carried out in 5-5 randomly selected samples. Mann–Whitney U test, Wilcoxon rank sum test (alpha diversity), and PERMANOVA analysis (beta diversity) were performed. Results: In MRONJ samples, 185 anaerobic isolates, corresponding to 65 different species were identified (vs. 72 isolates, corresponding to 27 different species in the control group). The detection of Actinomyces spp. and ALOs was more common in MRONJ bone samples, based on traditional culture (65.7% vs. 17.1%; p < 0.001) and PCR (82.9% vs. 37.1%; p < 0.001), respectively. The isolation of Fusobacterium spp. (22 vs. 7; p = 0.001), Prevotella spp. (22 vs. 6; p = 0.034), and Gram-positive anaerobic cocci (GPAC) (30 vs. 9; p = 0.016) was significantly more common in MRONJ patient samples. The microbiota of the controls’ bone samples were characterized by a considerable dominance of Streptococcus spp. and Veillonella spp, while the bacterial abundance rates were substantially more heterogeneous in MRONJ bone samples. Notable differences were not observed among the samples related to the abundance of Actinomyces in the bone microbiota. Conclusions: According to the “infection hypothesis”, alterations in the oral microbiome—with Actinomyces and ALOs being the most relevant—may play a key role in the development, aggravation, and progression of MRONJ. The timely detection of Actinomyces in necrotic bone is crucial, as it has important therapeutic implications.