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IntroductionEndometriosis is a common, benign, chronic inflammatory disease with multiple consequences, from chronic pain to systemic comorbidities and poor quality of life. As it usually affects people of reproductive age, one of the most distressing consequences is infertility, which can be only partly overcome by medically assisted reproduction. Poor outcomes are, in fact, frequent adverse events. As no definitive therapy exists for endometriosis-related infertility, affected women often tend to try either complementary and alternative medicine or self-management strategies to improve their quality of life, with the hope of also enhancing their fertility. Among available options, dietary interventions are commonly explored, even if no robust evidence is available on the optimal type of diet and its effects on reproductive outcomes. This trial will investigate whether an anti-inflammatory dietary intervention can improve fertility outcomes in women affected by endometriosis undergoing in vitro fertilisation (IVF).Methods and analysisThe DietAry interveNtion in ameliorating fertiliTy parameters in women with Endometriosis undergoing IVF (DANTE) study is a single-centre, randomised, controlled, non-pharmacological interventional trial in patients living with endometriosis who are infertile and require IVF. Participants will be allocated to either a 12-week intervention based on an anti-inflammatory diet or no diet before the beginning of controlled ovarian stimulation. Following baseline assessment, 438 participants aged <40 years with a diagnosis of infertility according to WHO criteria (ie, not conceiving after 12 months or more of regular unprotected intercourse) and a normal ovarian reserve will be randomly allocated to one of the two groups (1:1 ratio). In both groups, the dietary habits of participants will be assessed at baseline, and adherence to the intervention will be monitored throughout the study period via 24-hour recalls and food diaries. Participants will provide biological samples (peripheral blood, vaginal swabs and faeces) before and after the intervention to evaluate potential differences in inflammatory markers and microbiome composition between the two groups and across timepoints (before and after diet in the intervention group). Follicular fluid will be collected at the time of oocyte retrieval to describe potential difference in sex steroid levels. Patients will also complete questionnaires on quality of life, sexual function and symptom severity before and after the intervention to assess differences between the two groups and across time points. The primary outcome will be the rate of inadequate ovarian response (defined as the retrieval of ≤3 oocytes according to the Poseidon 2016 criteria) at the time of oocyte retrieval in the treatment versus the no-treatment groups. Secondary outcomes will include clinical pregnancy and live birth rates, IVF-related embryological outcomes, inflammatory marker levels in peripheral blood, vaginal and bowel microbiota features, steroid composition of follicular fluid, life quality and pain symptoms variation.Ethics and disseminationThe study has received ethics approval from Comitato Etico Territoriale Lombardia 3 (#5587_18.12.2024). Results will be presented in peer-reviewed journals and at international conferences.Trial registration numberNCT06885125.

During pregnancy crucial anatomic, physiologic, and metabolic changes challenge the mother and the fetus. The placenta is a remarkable organ that allows the mother and the fetus to adapt to the new metabolic, immunologic, and angiogenic environment imposed by gestation. One of the physiologic systems that appears to have evolved to sustain this metabolic regulation is mediated by peroxisome proliferator-activated receptors (PPARs). In clinical pregnancy-specific disorders, including preeclampsia, gestational diabetes, and intrauterine growth restriction, aberrant regulation of components of the PPAR system parallels dysregulation of metabolism, inflammation and angiogenesis. This review summarizes current knowledge on the role of PPARs in regulating human trophoblast invasion, early placental development, and also in the physiology of clinical pregnancy and its complications. As increasingly indicated in the literature, pregnancy disorders, such as preeclampsia and gestational diabetes, represent potential targets for treatment with PPAR ligands. With the advent of more specific PPAR agonists that exhibit efficacy in ameliorating metabolic, inflammatory, and angiogenic disturbances, further studies of their application in pregnancy-related diseases are warranted.

Vascular endothelial growth factor A (VEGF-A) is one of the main growth factors involved in placental vasculogenesis and angiogenesis, but its placental expression is still ambiguous. During in vitro cultures of primary term cytotrophoblasts, VEGF could not be detected in the supernatants by enzyme-linked immunosorbent assays (ELISA). One hypothesis is that VEGF is immediately and completely bound to its soluble receptor after secretion, and cannot be recognized by the antibodies used in the commercial ELISA kits. We decided to verify this hypothesis by measuring VEGF-A expression during in vitro cultures of primary term cytotrophoblasts. Term cytotrophoblasts were cultured under 21% and 2.5% O2 for 4 days. VEGF-A transcripts were quantified by real-time polymerase chain reaction. The proteins from cell lysates and concentrated media were separated by polyacrylamide gel electrophoresis (PAGE) under denaturing and reducing conditions, and VEGF-A immunodetected by western blotting. VEGF mRNA expression did not increase during in vitro cell differentiation under 21% O2, but slightly increased under 2.5% O2 only at 24 h. VEGF-A monomer was not detected in the cell lysates and in the concentrated supernatants, while a ~ 42 KDa band corresponding to the precursor L-VEGF was detected in all the cellular extracts. Isolated term villous cytotrophoblasts produce the L-VEGF precursor but they do not secrete VEGF-A even under low-oxygen tension. The question remains about the origin of VEGF in pregnancy but also about the biological role of L-VEGF, which can represent a form of storage for rapid VEGF secretion when needed.

SummaryIntroduction Cancers during pregnancy can be treated with chemotherapy after the first trimester but the treatment is associated with smaller placentas and an increased risk of stillbirth, fetal growth retardation and preterm delivery. We decided to assess the effect of several chemotherapeutic agents on placental development by using in vitro culture of human term cytotrophoblasts. Methods Cytotrophoblasts isolated from term placentas were cultured for 48 h and treated for 24 h with epirubicin, docetaxel, vinblastine, methotrexate, tamoxifen, 4-hydroxytamoxifen, and endoxifen. First, cell viability was assessed. Then, the effect of the treatment on trophoblast differentiation and placental angiogenesis was assessed by quantifying hCG and PlGF mRNA and protein expression. Finally, the expression of two efflux transporters, BCRP and MDR1 was investigated. Results Epirubicin only strongly decreased cell viability. Epirubicin, docetaxel, and vinblastine inhibited HCGB and PlGF expression while methotrexate, tamoxifen and its two metabolites increased it. BCRP was essentially expressed in syncytiotrophoblasts and MDR1 in undifferentiated cytotrophoblasts. Their expression was not affected by the drugs but vinblastine increased BCRP mRNA expression by 2.8-fold. Discussion The most commonly used chemotherapeutic drugs are well supported in vitro by syncytiotrophoblasts, except for epirubicin, which was very cytotoxic. Chemotherapy perturbed the expression of genes normally upregulated during placental differentiation and angiogenesis but not the expression of the drug transporters. Further studies looking at the effect of combination therapy and the transporter capacities to reject the drugs will be needed to better define the effects of chemotherapy on placental development and function.

Background Heart failure (HF) with preserved ejection fraction (HFpEF) is increasingly prevalent worldwide due to aging and comorbidities. Epicardial adipose tissue (EAT), favored by diabetes and obesity, was shown to contribute to HFpEF pathophysiology and is an emerging therapeutic target. This study explored the relationship between ventricular EAT measured by cardiovascular magnetic resonance (CMR), metabolic factors, and imaging characteristics in controls, pre-HF patients, and HFpEF patients. Methods Patients from a Belgian cohort enrolled from December 2015 to June 2017 were categorized by HF stage: pre-HF (n = 16), HFpEF (n = 104) and compared to matched controls (n = 26) and to pre-HF (n = 191) from the Beta3-LVH cohort. Biventricular EAT volume was measured in end-diastolic short-axis cine stacks. In the Belgian cohort, associations between EAT, HF stage, and various biological and imaging markers were explored. The clinical endpoint was a composite of mortality or first HF hospitalization in the HFpEF group. Results EAT significantly differed between groups, with higher values in HFpEF patients compared to pre-HF and controls (72.4 ± 20.8ml/m 2 vs. 55.0 ± 11.8ml/m 2 and 48 ± 8.9ml/m 2 , p < 0.001) from the Belgian cohort and to pre-HF (52.0 ± 15.0 ml/m 2 , p < 0.001) from the Beta3-LVH cohort. Subsequent analyses focused on the Belgian cohort. In contrast to atrial fibrillation, diabetes prevalence and body mass index (BMI) did not differ between pre-HF and HFpEF patients. Multivariable logistic regression and random forest classification identified EAT, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and H 2 FPEF score as strong markers of HFpEF status. EAT was significantly correlated with H 2 FPEF score (r = 0.41, p = 0.003), BMI (r = 0.30, p < 0.001), high‐sensitive troponin T (r = 0.41, p < 0.001), NT-proBNP (r = 0.37, p < 0.001), soluble suppression of tumorigenicity-2 (sST2) (r = 0.30, p < 0.001), E/e’ ratio (r = 0.33, p < 0.001), and left ventricular global longitudinal strain (r = 0.35, p < 0.001). In HFpEF patients, diabetes, ischemic cardiomyopathy, and elevated sST2 were independently associated with elevated EAT. In contrast with diabetes and BMI, increased EAT was not associated with prognosis. Conclusions EAT assessed by CMR was significantly higher in HFpEF patients compared to controls and pre-HF patients, irrespective of diabetes and BMI. EAT was moderately associated with HFpEF status. HFpEF patients with elevated EAT exhibited a marked diabetic, ischemic, and inflammatory profile, highlighting the potential role of drugs targeting EAT. Trial registration Characterization of Heart Failure With Preserved Ejection Fraction; Assessment of Efficacy of Mirabegron, a New beta3-adrenergic Receptor in the Prevention of Heart Failure (Beta3_LVH). Trial registration number ClinicalTrials.gov. Identifier: NCT03197350; NCT02599480. Graphical abstract