Search Results (2,259)

Chronic histiocytic intervillositis (CHI) is a placental lesion characterized by an inflammatory response, significantly influencing maternal and fetal outcomes. This study aims to develop a comprehensive morphologic atlas detailing the localization of fetal and maternal macrophages within the context of CHI. We employed immunohistochemical and multiplexing techniques to analyze placental samples, identifying expression patterns and spatial distribution of key macrophage markers, including CD68, CD163, CD14, and HLA-DR. The results revealed a marked accumulation of activated macrophages in both the intervillous space and villous stroma, with distinct differences in morphology and immunophenotype of fetal Hofbauer cells versus maternal macrophages. Our findings contribute to a better understanding of the immune landscape in CHI and provide a valuable resource for further research into placental immune dynamics. By establishing this morphologic atlas, we aim to enhance diagnostic and therapeutic strategies for affected pregnancies, thereby improving the diagnostic approach and making it more straightforward to recognize CHI histologically. Full article

Preeclampsia (PE) is a leading cause of maternal and perinatal complications and is classified by early or late onset according to the gestational age. The complex pathogenesis of PE involves placental ischemia, oxidative stress, angiogenic imbalance, and inflammation, all of which contribute to impaired placentation and widespread maternal endothelial dysfunction. These mechanisms drive hypertension, multi-organ involvement, and increased long-term cardiovascular risk. Parallel research highlighted the role of the NLRP3 inflammasome, a multiprotein complex that, upon activation, increases the gene expression, processing, and release of the pro-inflammatory cytokines IL-1β and IL-18. The NLRP3 pathway is markedly upregulated in placentas from pregnant women with PE, where endogenous danger signals stimulate inflammasome activation and amplify inflammation. Increasing evidence indicates that microRNAs (miRNAs) help regulate inflammatory processes, including the NLRP3 inflammasome, thereby affecting placental function and maternal adaptation. Although several immunoregulatory miRNAs may influence NLRP3 activity, their specific contribution to inflammasome regulation in PE remains insufficiently understood. Understanding these interactions could reveal new therapeutic targets for PE. In this narrative review, we explore the interconnected roles of endothelial dysfunction, inflammasome activation, and miRNA-mediated regulation in the pathogenesis of PE. Full article

The hypothalamic–pituitary–adrenal (HPA) axis coordinates metabolic, immune, and behavioral responses to a changing environment. Its molecular effectors are the nuclear receptors for glucocorticoids and mineralocorticoids (the GRs/MRs), encoded by nr3c1/nr3c2. The MR serves as the high-affinity sensor of basal hormone concentrations, whereas the GR amplifies the stress response and mediates negative feedback. Despite their shared domain architecture, the receptors have diverged functionally: isoform composition, post-translational modifications, and the complement of co-regulators together determine which genes are activated or repressed in a given tissue at a given time. The regulation of the HPA axis activity is a major determinant of embryonic development. Pregnancy adds a placental control layer that meters maternal signals: 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) in the syncytiotrophoblast inactivates cortisol, whereas 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) can regenerate it, and systemic buffering by transcortin (cortisol-binding globulin, CBG) limits the free hormone fraction. Under stress, inflammation, or hypoxia, this barrier weakens, exposing the fetus to stronger glucocorticoid pulses during windows of heightened vulnerability for brain and immune development. Such overexposure not only reshapes ongoing transcription but is also epigenetically inscribed: the methylation of alternative nr3c1 promoters, the remodeling of histones, and the shifts in ncRNA profiles recalibrate the axis sensitivity for the long term. At the phenotypic level, this manifests as variability in stress reactivity, cognitive and affective trajectories, and an immune and metabolic risk across later ontogeny. In this review, we integrate evidence on the structure and functions of the GR, the mechanisms of its post-translational and epigenetic regulation, and the role of the placenta, to provide a coherent framework for understanding the multifaceted consequences of prenatal stress and to identify potential targets for early prevention. Full article

Retained placenta (RP) is a significant postpartum complication in dairy cows. Although abnormal estradiol (E₂) levels are implicated, the underlying cellular mechanisms remain poorly defined. Through RNA-seq analysis of postpartum blood from cows with or without RP, we identified Serum and Glucocorticoid-regulated Kinase 1 (SGK1) as a differentially expressed gene candidate. Analysis of fetal cotyledonary tissues revealed that SGK1 expression was significantly elevated in these tissues, concomitant with markers of suppressed apoptosis, increased levels of tight junction proteins, and an inhibited epithelial–mesenchymal transition (EMT) phenotype. To explore a potential mechanistic link between E₂ and these cellular alterations, we investigated the E₂-SGK1 axis in bovine endometrial epithelial cells in vitro. E₂ treatment upregulated SGK1 expression, reduced apoptosis, increased tight junction protein levels, and suppressed EMT. Conversely, SGK1 knockdown induced apoptosis, disrupted tight junctions, and impaired EMT. Notably, E₂ could not rescue the apoptosis and EMT alterations in SGK1-knockdown cells, indicating that SGK1 is a critical mediator of these E₂ effects in this cellular model. Based on these initial correlative findings in tissues, combined with the subsequent mechanistic experiments in cells, we propose a novel model whereby dysregulation of the E₂- SGK1 axis could contribute to RP pathogenesis by stabilizing the placental interface. Our findings provide the first experimental evidence linking SGK1 to RP and establish a foundation for future in vivo validation. Full article

Preeclampsia, affecting 3–8% of pregnancies worldwide, remains a leading cause of maternal and perinatal morbidity and mortality. This review synthesizes current molecular, immunological, and hemodynamic evidence to clarify the central role of oxidative stress in the pathogenesis of preeclampsia. Placental oxidative stress, resulting from an imbalance between reactive oxygen species (ROS) generation and antioxidant defenses, secondary to placental hypoxia due to various etiologies especially impaired spiral artery remodeling, drives mitochondrial dysfunction in trophoblasts, ischemia–reperfusion injury, inflammatory pathway activation, and disruption of angiogenic homeostasis, thereby promoting systemic inflammation. Key regulatory pathways, including Nrf2/HO-1, NF-κB, PI3K/Akt, and HIF-1α, together with biomarkers such as malondialdehyde, 8-isoprostane, and the sFlt-1/PlGF ratio, characterize this redox imbalance. Although experimental studies demonstrate promising effects of targeted antioxidants, mitochondria-directed agents, and pathway-specific modulators, clinical translation remains limited, as non-specific antioxidants such as vitamins C and E have failed to prevent preeclampsia. Future advances will likely depend on mechanism-based therapies initiated early in pregnancy and tailored to the disease subtype and biomarker profiles. Collectively, this review provides an integrated mechanistic framework and highlights critical knowledge gaps that must be addressed to enable the development of effective preventive and therapeutic interventions for preeclampsia. Full article

Cartilage is an important yet vulnerable tissue with limited self-healing capacity, where damage often progresses to joint degeneration, which eventually leads to severe osteoarthritis (OA). Current tissue engineering strategies focus on biocompatible scaffolds for cartilage regeneration, particularly amnion (or amniotic membrane), emerging as a promising biomaterial due to its wide availability, low immunogenicity, and naturally derived microenvironment that is advantageous for cartilage regeneration. This systematic review aims to evaluate the existing evidence on the efficacy of amnion as a tissue scaffolding material for cartilage regeneration in both preclinical and clinical studies. Using terms such as “cartilage damage”, “cartilage injuries”, “amnion” and “amniotic membrane”, 19 relevant studies were identified across three major databases (PubMed, Scopus and Web of Science) until 25 December 2025. All preclinical and clinical studies that utilized amnion for cartilage repair or as cartilage tissue engineering scaffolding materials were included. Evidence quality was assessed using the OHAT and MINORS risk of bias tool. This study is prospectively registered in the PROSPERO database under the ID 1178444. The findings consistently indicate that amniotic scaffolds, regardless of processing methods or cell seeding, yield favorable outcomes without adverse effects across different species. In vitro analysis revealed that treatment groups with amnion show better cell attachment, viability, and proliferation, and higher content of cartilage-related markers expressed by the seeded cells, either chondrocyte, bone marrow-derived mesenchymal stem cells (MSCs), adipose tissue-derived MSCs, placenta-derived MSCs, umbilical cord-derived MSCs, amniotic MSCs or amniotic epithelial cells. In in vivo and ex vivo studies, amnion-treated groups demonstrated improved quality of the treated cartilage, with better integration, as indicated by higher histological scores and the presence of type II collagen (COL-II). There was an inconsistency in the reporting of cartilage defect dimensions in the in vivo models across the different studies. Nevertheless, the outcome measurements were consistently reported with histological analysis, with or without International Cartilage Repair Society (ICRS) scoring and immunohistochemistry (IHC) analysis, across the studies. Clinically, most subjects show improvement in the Knee Injury and Osteoarthritis Outcome Score (KOOS) Sports and Recreation score and KOOS Quality of Life score, as well as reduced Visual Analogue Scale (VAS) average and maximum pain scores. In conclusion, preclinical and clinical studies support amnion as an ideal scaffold material for cartilage tissue engineering and regeneration. Future research should focus on optimizing and standardizing amnion scaffold preparation at a production scale to facilitate the translation of these positive outcomes into clinical applications. This study is funded by the Ministry of Higher Education Malaysia via Prototype Research Grant Scheme (PRGS/1/2021/SKK01/UM/02/1) and UM International Collaboration Grant—2023 SATU Joint Research Scheme Program: ST007-2024. Full article

The high concentration of the inflammatory cytokine IL-36 in the serum of patients with type 2 diabetes mellitus (T2DM), along with the reduced renal damage observed in IL-36R knockout mice following ischemia–reperfusion-induced acute kidney injury, suggests a significant association between IL-36 activity and diabetic complications such as diabetic nephropathy (DN). It is also known that minor structural alterations in glomerular tissues can lead to changes in blood vessel pressure, potentially contributing to the development of DN, with inflammation acting as a triggering factor. However, further studies are needed to confirm this relationship. In this study, we observed that mesangial (MES-SV40) cells cultured under high-glucose conditions produced IL-36α in a dose-dependent manner. This cytokine production was also detected in mesangial cells from the glomerular tissues of mice with a high-calorie diet-induced T2DM, whereas healthy mice did not show such expression. In addition, we observed that mouse endothelial cells (SVECs) showed increased tubule formation in co-culture with MES-SV40 cells that had been previously exposed to 30 mmol/L glucose, as well as with the supernatant from these cells. IL-36R expression was confirmed in endothelial cells, as well as the angiogenic effect of IL-36α. Given that elevated VEGF levels have been reported in patients with DN by other authors, our results suggest that IL-36 produced by mesangial cells under high-glucose conditions may promote angiogenesis in glomerular tissues, potentially initiating the development of diabetic nephropathy. Full article

Dedifferentiation—the acquisition of an early developmental state—is a hallmark of cancer. However, the underlying mechanisms that lead to cancer-associated dedifferentiation are not fully understood. Transposable elements (TEs) are becoming increasingly recognised as important regulators of development and disease. The recruitment of TE sequences has played an important role in placental evolution, and TE-derived genes play critical roles in placental development. Although important biological differences exist between tumours and the placenta, the placenta shares certain features with tumours, including the capacity to invade surrounding tissue and modulate the maternal immune response. In this regard, TEs have been implicated in cancer development, and are documented to contribute to oncogenesis through multiple different mechanisms. Moreover, cancers reacquire an epigenetic landscape, which is reflective of early development, and which corresponds to increased phenotypic plasticity, including facilitating the activation of early developmental genes. Many cancers can repurpose developmental genes, including TE-associated genes, which may contribute to pathways involved in invasion and metastasis. Determining whether TE activation is a consequence of broader epigenetic reprogramming or actively contributes to dedifferentiation will be important for understanding cancer biology and may facilitate improvements in cancer diagnosis and treatment. Full article

To reduce pressure on capture fisheries, sustainable aquaculture must decrease its dependency on fish meal and fish oil. Microalgae are a promising substitute due to their complete nutritional profile and low-footprint production process. This study examined the use of the cyanobacterium Limnospira maxima (commercially known as Spirulina) as a partial substitute for fish meal in feed for juvenile Nile tilapia (Oreochromis niloticus). We developed isoproteic (36%) and isoenergetic (3000 kcal kg⁻¹) fish feed formulations containing 0% (control), 10%, 20%, 30%, or 40% L. maxima dry biomass. The experimental diets were then fed to 360 juvenile O. niloticus (1.32 ± 0.35 g) for 85 days using a randomized experimental design. The hepatic, intestinal, and muscle (fillet) tissues of the fish were collected for morphophysiological, fatty acid, and proteomic analyses. The intestinal coefficient, number of intestinal villi, villus height, and hepatosomatic index were essentially the same for all treatments (p > 0.05). Treatments containing 20–30% L. maxima exhibited a higher degree of unsaturation and better dietary fat quality. A greater abundance of the enzymes SOD, GSR, PRX1, and PLD3 in the experimental groups indicated higher antioxidant activity, whereas a greater abundance of acyl-CoA dehydrogenases indicated better use of fatty acids as an energy source. These trends were more evident in the 20–30% inclusion range. Thus, adding L. maxima to fish feed improves farming performance, fish health, and product quality. The results encourage the use of microalgae to promote more sustainable aquaculture. Full article

Background: Autophagy is a conserved intracellular degradation pathway essential for maintaining cellular homeostasis by recycling damaged organelles and proteins. Dysregulation of autophagy has been implicated in pregnancy-related complications such as preeclampsia and fetal growth restriction, underscoring its importance in maternal and fetal health. However, the autophagy status in the placental tissue of COVID-19-infected pregnant women remains unknown. Objective: To investigate autophagy activity in term placentas from pregnant women infected with COVID-19 compared to those from uninfected control pregnant women. Methods: In this prospective cross-sectional single-center study, 15 COVID-19-positive and 15 COVID-19-negative term pregnant women who delivered at Sultan Qaboos University Hospital between January 2020 and December 2022 were included. Immediately after delivery, the placental tissue samples were collected and assessed for autophagy activity using immunohistochemistry for LC3B and p62 markers, histopathological examination, and transmission electron microscopy. The proportion and intensity of LC3B and p62 staining were quantified. Statistical analysis was performed using the Mann–Whitney U test. Results: There was a significant reduction in p62 and LC3B expression in both the proportion and intensity in COVID-19 placentas compared to the control group. The proportion of p62 (p = 0.001) and LC3B (U = 46.000, p = 0.003) was significantly reduced in infected placentas. Similarly, intensity levels of both markers showed significant differences (p < 0.05), supporting the evidence of reduced LC3B/p62, suggesting autophagy modulation in COVID-19 patients’ placentas. Additionally, abnormal ultrastructural changes were observed in COVID-19–positive placentas, including mitochondrial injury, endoplasmic reticulum stress, microvillus loss, and basement membrane thickening. Conclusion: The study results from a limited sample size demonstrate a significantly altered autophagy flux in the placental tissues of term pregnant women with COVID-19 infection. These findings highlight the potential impact of COVID-19 infection on placental function and fetal development and underscore the need for further investigation into autophagy-modulating strategies to improve maternal–fetal health. Full article

Background/Objectives: Dichorionic triamniotic (DCTA) triplet pregnancies are associated with increased rates of placenta-specific complications primarily attributed to vascular anastomoses in the monochorionic (MC) pair. Selective fetal reduction to twins (of one of the MC pair) is a complex and not a widely available procedure. Multifetal reduction (MFR) to singleton pregnancy can reduce adverse pregnancy outcomes but is controversial due to medico-legal and socio-ethical issues. The aim of this study is to identify the rate of miscarriage < 24 weeks or preterm birth < 34 weeks following MFR to singleton pregnancy in DCTA triplets and compare the results with expectant management. Methods: This systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and registered in the Prospective Register of Systematic Reviews System (ID: CRD42023422585). Results: Overall, from 21 citations of relevance, 6 studies with a total of 548 DCTA triplet pregnancies fulfilled the inclusion/exclusion criteria. In comparison with expectant management (n = 336), meta-analysis demonstrated that MFR to singleton pregnancy (n = 212) was associated with a lower rate (9.4% vs. 48.5%) of preterm birth (RR = 0.19, 95%CI 0.07–0.51), whereas the rate of miscarriage (14.6% vs. 9.2%) did not significantly increase (RR = 1.53, 95%CI 0.91–2.55). Conclusions: In DCTA triplet pregnancies, MFR to singleton pregnancy was associated with a reduced preterm birth rate and not associated with an increased miscarriage rate. Given the fact that the MC pair is reduced only to lower the rate of preterm birth, appropriate counselling and justification are important. In the absence of randomized controlled trials, data from systematic reviews are the best available evidence for counseling on the different management options. Full article

Three-dimensional (3D) organoid and co-culture models have emerged as transformative tools for studying human endometrial function, implantation, and placental development, overcoming key limitations of animal and two-dimensional in vitro systems. This review synthesises available information of recent advances in endometrial epithelial organoids (EEOs), trophoblast organoids (TBOs), and increasingly complex co-culture platforms incorporating stromal, vascular, and trophoblast compartments to model epithelial–stromal crosstalk, decidualisation, angiogenesis, and embryo implantation. Emerging developments include assembloid systems, synthetic and semi-synthetic extracellular matrices, and microfluidic organ-on-a-chip technologies that enable long-term culture, hormonal responsiveness, and patient-specific modelling. These approaches have recapitulated key features of the mid-secretory endometrium, placental villous architecture, trophoblast differentiation, and early implantation events while revealing disease-associated dysfunctions in conditions such as endometriosis, adenomyosis, polycystic ovarian syndrome, and endometrial cancer. Despite significant progress, current models remain limited by incomplete cellular diversity, polarity constraints, and challenges in fully modelling immune and vascular interactions. Collectively, emerging 3D organoid and co-culture systems provide physiologically relevant platforms to interrogate human reproductive biology, elucidate mechanisms underlying implantation failure and placental disease, and support the development of personalised therapeutic strategies to improve reproductive outcomes. Full article

This narrative review presents an updated overview of the etiology, pathophysiology, diagnostic approaches, and management strategies for Placenta Accreta Spectrum (PAS), with emphasis on clinical implications and current gaps in evidence. PAS is associated with substantial maternal morbidity and mortality, with reported maternal mortality rates approaching 7%. Affected patients often experience prolonged hospitalization, repeated surgical interventions, and long-term psychological and emotional consequences. The development of PAS is primarily attributed to impaired decidualization in areas of uterine scarring, resulting in abnormal adherence or invasion of chorionic villi into the myometrium. Optimal outcomes in high-risk pregnancies depend on early antenatal identification using characteristic pathological and imaging findings. Current evidence supports planned cesarean hysterectomy as the safest and most definitive treatment for most patients, whereas conservative and uterus-preserving approaches should be reserved for carefully selected cases managed in specialized centers. Further progress in PAS management requires standardized diagnostic criteria, prospective evaluation of conservative strategies, and improved access to multidisciplinary expertise. Full article

Recognition and binding to β-galactose-containing carbohydrates and lipids are crucial for several fundamental biological processes that are mediated primarily by a family of proteins known as galectins (S-type lectins). Galectins in the human placenta regulate critical processes such as maternal–fetal immune tolerance, trophoblast invasion, vascular remodeling and angiogenesis, ensuring proper fetal development and preventing pregnancy complications such as preeclampsia and miscarriage. Gestational diabetes mellitus (GDM) is a widespread complication of pregnancy, affecting approximately 1 in 7 pregnancies, and its incidence is increasing globally, indicating a particularly strong association with the obesity pandemic. Profiles of placental expression and distribution of individual galectins significantly change during the course of GDM. This is accompanied by placental dysfunction, which is especially severe with poor glycemic control. The aim of this review is to present the current state of knowledge on the involvement of abnormal galectin signaling in the pathomechanisms of GDM-associated placental dysfunction. Further research is needed to determine whether changes in placental galectins occur secondary to metabolic abnormalities in GDM or are involved as a primary cause. Galectins present in placental tissue and serum should be validated as potential biomarkers of GDM. Full article

Background: SARS-CoV-2 infection during pregnancy has been associated with systemic inflammatory responses and placental pathology; however, the molecular mechanisms underlying placental involvement remain incompletely understood. The endocannabinoid system plays a critical role in placental development, immune regulation, and vascular homeostasis. Materials and Methods: Placental tissues were obtained from 20 healthy pregnant women and 20 women with confirmed SARS-CoV-2 infection who had recovered by the time of delivery. Demographic and laboratory parameters were recorded. Histopathological evaluation was performed using hematoxylin and eosin staining. Immunohistochemical analysis of cannabinoid receptor 1 (CNR1) and cannabinoid receptor 2 (CNR2) expression was conducted, supported by quantitative digital image analysis using QuPath. Network-based protein–protein interaction and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to explore potential molecular mechanisms. Results: COVID-19-positive placentas exhibited prominent histopathological alterations, including increased fibrinoid deposition, syncytial knot formation, vascular congestion, and intervillous inflammatory cell infiltration. Systemic inflammatory and coagulation markers, particularly neutrophil percentage, C-reactive protein, D-dimer, and fibrinogen levels, were significantly elevated in the COVID-19 group. CNR1 and CNR2 expressions were markedly increased across multiple placental compartments, including decidual cells, trophoblastic layers, syncytial knots, and Hofbauer cells. Quantitative digital analysis confirmed significant upregulation of both receptors. Bioinformatic analysis revealed enrichment of endocannabinoid signaling, cAMP-related pathways, and inflammatory mediator regulation of TRP channels. Conclusions: The findings indicate that SARS-CoV-2 infection is associated with coordinated inflammatory, structural, and molecular alterations in the placenta. Upregulation of CB1 and CB2 suggests an active involvement of the endocannabinoid system in placental immune and vascular responses to COVID-19, highlighting its potential relevance for understanding placental pathology associated with maternal viral infections Full article