PROBLEM:Tokishakuyakusan (TSS) is a traditional Japanese Kampo medicine widely used to support pregnancy; however, its molecular mechanisms remain poorly understood. This study aimed to elucidate the progesterone-related immunomodulatory mechanisms underlying the pregnancy-supportive effects of TSS using a mouse model of progesterone withdrawal induced by mifepristone. METHODS:Pregnant mice were fed either a control diet or a diet containing 1% TSS from mating until late gestation. On day 15 postcoitus, all mice received low-dose mifepristone to induce functional progesterone withdrawal. Cytokine and chemokine profiles in serum, corpus uteri, and placenta were analyzed using multiplex assays, and uterine expression of progesterone-responsive and inflammatory genes were evaluated by real-time RT-PCR. RESULTS:Mifepristone administration induced a systemic proinflammatory response, characterized by increased serum levels of G-CSF, IL-6, KC, and MCP-1. TSS administration increased G-CSF without affecting fetal number, fetal weight, or placental weight. In the corpus uteri, TSS significantly suppressed IL-6 protein expression, whereas placental cytokine profiles were largely unaffected. Furthermore, TSS significantly increased uterine mRNA expression of the progesterone-responsive anti-inflammatory molecules secretory leukocyte peptidase inhibitor (SLPI) and progranulin (PGRN). CONCLUSIONS:These findings suggest that TSS mitigates inflammation associated with progesterone withdrawal by suppressing uterine IL-6 and increasing the expression of progesterone-responsive anti-inflammatory molecules such as SLPI and PGRN. These findings suggest that TSS may modulate progesterone-responsive anti-inflammatory pathways through increased expression of SLPI and PGRN while suppressing uterine IL-6.
PROBLEM:Microchimerism in the brain is a common phenomenon, where in cells cross between mother and fetus during pregnancy, and persist for decades. It has been studied primarily within reproductive immunology and transplantation medicine. The relevance of microchimerism to central nervous system biology, neurological disease, and experimental chimeric modelling has received comparatively little systematic attention. This review sought evidence across the biology of feto-maternal microchimerism, its association with neurological disease, and the emerging field of experimental chimeric brain modelling, to extrapolate a cohesive mechanistic framework. METHOD:Research articles in reproductive immunology, neurodevelopment, and neurodegeneration were gathered to assess the potential roles of fetal microchimeric cells (FMc) in brain health and disease. By combining natural microchimerism with experimental chimeric models, a framework for understanding how nonself cells influence the maternal brain was extrapolated and critical mechanisms identified. Searches were conducted across PubMed/MEDLINE, Scopus, and Google Scholar using a dual-concept Boolean. RESULTS:The literature reviews show that microchimeric cells cross the blood-brain barrier (BBB), adopt neural and glial phenotypes in the maternal brain parenchyma, and exhibit injury-responsive recruitment in preclinical models. Reciprocally, maternal microchimeric cells (MMc) are present in the offspring brain, where they have been found adopting neural and immune-lineage phenotypes in experimental models. These findings raise the possibility that bidirectional microchimerism influences susceptibility to neurological disease, modulates neuroimmune signaling, and contributes to endogenous repair, although causal mechanisms remain unresolved. Experimental chimeric brain models have extended these principles into therapeutic contexts. Establishing the functional mechanism and directionality requires more prospective longitudinal cohort studies and transcriptional profiling at single-cell resolution in microchimeric brain-resident populations.
PROBLEM:Patients with threatened preterm labor (PTL) are treated with antibiotics, corticosteroids, and magnesium sulfate to mitigate infection, promote fetal lung maturation, provide fetal neuroprotection and overall minimize the impact of prematurity on the neonate. However, the effect of these drugs on the placental inflammatory profile is unknown even though these are given systemically and reach the placenta. We evaluated their action in an ex vivo model of placental inflammation. METHOD OF STUDY:Placental explants from uncomplicated pregnancies were exposed to lipopolysaccharide (LPS) ± azithromycin, betamethasone, and/or magnesium sulfate. Production (lysate) and secretion (supernatant) of pro- and anti-inflammatory cytokines were assessed by ELISA. RESULTS:Both pro- and anti-inflammatory cytokines were increased by LPS versus untreated. Azithromycin, or magnesium sulfate did not alter the inflammatory profile by themselves nor when added at the same time or 24 h after LPS. Betamethasone decreased both pro- and anti-inflammatory cytokines only when administered at the same time as LPS, without any effects if delayed. CONCLUSIONS:Therapeutic interventions classically used for preterm labor (PTL) do not impact the placental inflammatory profile by themselves or in the context of an ex vivo placental explants model of LPS-induced inflammation, except for betamethasone when administered concurrently with LPS.
Preeclampsia (PE) affects 2%-8% of pregnancies globally and remains a leading cause of maternal and perinatal mortality. A central clinical gap is the absence of analytically and clinically validated non-invasive biomarkers capable of predicting PE before symptom onset. Current clinical tools, including angiogenic markers (sFlt-1/PlGF ratio) and first-trimester risk algorithms, have limitations that underscore the need for complementary approaches. Placental extracellular vesicles (EVs)-small particles released predominantly by syncytiotrophoblast cells-are implicated across PE pathophysiology. Circulating total small EV (sEV) concentrations, typically 30-150 nm and isolated by differential centrifugation or size-exclusion chromatography, are measurably elevated in maternal circulation from the first trimester in women who develop PE; this operational, size- and isolation-based definition does not by itself establish placental origin, which requires placental-attribution markers (e.g., PLAP, syncytins) discussed in Section 2. Their molecular cargo, encompassing microRNAs (miR-210, miR-15a-5p, miR-520a-5p, miR-146a-5p, miR-93-5p), anti-angiogenic proteins (sFlt-1, sEng), and hypoxia markers (HIF-1α), reflects placental pathophysiology. Recent evidence has expanded the known pathophysiological reach of placental EVs: beyond endothelial dysfunction and angiogenic imbalance, they are now implicated in blood-brain barrier disruption via claudin-5 (CLDN5) downregulation, supporting a plausible mechanistic link to neurological complications of PE. Proteomic profiling of EV fractions identifies molecularly distinct PE subtypes, enabling investigational subtype discrimination beyond current clinical criteria. Recent in vivo proof-of-concept evidence in a rat model demonstrates that amniotic fluid-derived EV-associated miR-146a-5p ameliorates PE phenotypes, opening a preclinical therapeutic avenue. This narrative review synthesises evidence from a structured PubMed/MEDLINE and Scopus search covering 2017-March 2025 on placental EV biogenesis, cargo heterogeneity, immune modulation, organ-specific pathological consequences, and translational potential as first-trimester liquid biopsy candidates. Methodological standardization challenges and future research priorities are discussed.
OBJECTIVE:Venous thromboembolism (VTE) remains an important cause of maternal morbidity and mortality, yet the diagnosis of deep vein thrombosis (DVT) during pregnancy is challenging because clinical symptoms overlap with physiological gestational changes and D-dimer specificity is reduced. This study evaluated the association between complete blood count-derived systemic inflammatory indices and pregnancy-associated DVT. METHODS:This retrospective case-control study included 36 pregnant women with Doppler ultrasonography-confirmed DVT and 36 healthy pregnant controls matched for maternal age and gestational age. Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), and aggregate index of systemic inflammation (AISI) were calculated from routine complete blood counts. Univariable and multivariable Firth penalized logistic regression analyses were performed, adjusting for body mass index, history of cesarean delivery, and varicose veins. Elastic net penalized regression was used for variable selection. Gestational age-stratified sensitivity analyses, false discovery rate correction, receiver operating characteristic (ROC) analyses, and a supplementary trimester-specific D-dimer threshold analysis were also performed. RESULTS:Women with DVT had higher NLR, SII, SIRI, AISI, and D-dimer levels than controls, whereas PLR and MLR did not differ significantly. After false discovery rate correction, NLR, SII, SIRI, and AISI remained statistically significant. In multivariable Firth regression, NLR, SII, and D-dimer were independently associated with DVT. Elastic net analysis identified NLR and SII as the most informative inflammatory indices. ROC analyses showed moderate discriminatory performance for NLR and SII, either alone or combined with D-dimer. The gestational age-stratified analyses showed a consistent direction of association, while trimester-specific D-dimer thresholds increased specificity but substantially reduced sensitivity in this cohort. CONCLUSION:NLR and SII were associated with pregnancy-associated DVT and may reflect the thrombo-inflammatory component of this condition. However, the findings are exploratory and hypothesis-generating. These indices should be considered only as adjunctive markers within the existing diagnostic workflow, not as standalone diagnostic tools. Prospective studies using standardized sampling and pregnancy-adapted D-dimer strategies are needed before clinical implementation.
Despite major advances in biomedical HIV prevention strategies, almost 50% of the 1.3 million new HIV infections in 2024 occurred in women and girls through heterosexual transmission. Choice in HIV prevention modalities is needed throughout a women's lifespan to increase pre-exposure prophylaxis uptake; however, there is a paucity of topical, on-demand options. To establish HIV infection, the virus translocates across the epithelial barrier of the upper and lower female reproductive tract to infect CD4 + HIV target cells in the submucosa. The vaginal microbiome modulates this process. Women colonised with an optimal Lactobacillus-dominated vaginal microbiota are more protected against acquiring HIV compared to women with a non-optimal vaginal microbiota including bacterial vaginosis (BV), characterised by an overgrowth of diverse anaerobes and a paucity of beneficial lactobacilli. Optimal Lactobacillus spp. produce ∼1% lactic acid, which in women with a Lactobacillus-dominant microbiota acidifies the vaginal pH to less than 4.5, inactivates HIV, exerts antimicrobial effects against BV-associated bacteria, directly inhibits inflammatory responses elicited from cervicovaginal epithelial cells and blocks HIV translocation in vitro. Beneficial properties of optimal vaginal lactobacilli and/or lactic acid can potentially be exploited in vaginal delivery strategies to help prevent vaginal dysbiosis and its adverse sexual and reproductive outcomes including HIV.
PROBLEM:Inflammation contributes to spontaneous preterm birth, yet mechanisms regulating trophoblast inflammatory responsiveness remain unclear. Interleukin-1 beta (IL1β) is a potent mediator of labor-associated inflammation, but the role of its accessory receptor, IL-1 receptor accessory protein (IL-1RAP), at the maternal-fetal interface is poorly understood. METHOD OF STUDY:IL-1RAP expression and localization were assessed in preterm chorioamniotic membranes with or without intra-amniotic inflammation. Decidual regulation of trophoblast IL1RAP was evaluated in primary trophoblasts, and gain- and loss-of-function studies in HTR8/SVneo cells tested its role in IL-1β-induced inflammatory signaling. RESULTS:IL1RAP expression was increased in fetal membranes from inflammation-associated preterm labor and IL-1RAP localized prominently to extravillous trophoblasts. Decidual cell-conditioned media increased trophoblast IL1RAP expression. IL1RAP overexpression enhanced basal and IL-1β-induced expression of inflammatory mediators, including TNF, IL1B, IL6, and CXCL8/IL8, whereas IL1RAP silencing most consistently attenuated IL-1β-induced TNF expression. CONCLUSIONS:These findings identify trophoblast IL-1RAP as an amplifier of IL-1β-mediated inflammatory signaling and support further investigation of IL-1RAP in inflammation-associated preterm birth.
PROBLEMS:Pregnancy is a sensitizing event for human leukocyte antigen (HLA) alleles, as the fetus, acting as a semi-allograft, expresses maternal and paternal haplotypes in a codominant manner. Consequently, the mother may develop anti-HLA antibodies directed against the paternal haplotype. However, unlike in organ transplantation, this sensitization is not usually associated with fetal rejection in multiparous women, raising a central question in reproductive immunology: How is maternal-fetal tolerance achieved and maintained? METHOD OF STUDY:This review examines the influence of the HLA system on the immunological mechanisms underlying maternal-fetal tolerance. RESULTS:Accumulating evidence suggests that this phenomenon results from a complex network of cellular and molecular interactions. The roles of non-classical HLA molecules, particularly HLA-G, the modulation of NK activity via KIR receptors, and the expansion of regulatory T cells, which contribute to the maintenance of systemic immunological tolerance, are highlighted. In parallel, the relevance of anti-HLA antibodies and polymorphisms in HLA regulatory regions in susceptibility to gestational complications has been investigated. CONCLUSION:It considers how insights from reproductive immunology may inform related fields such as transplantation and oncology.
INTRODUCTION:Male infertility is a complex condition affected by multiple anatomical, physiological, and biochemical factors. Among the most commonly risk factors are leukocytospermia and varicocele, which are associated with increased oxidative stress and affected sperm function. OBJECTIVE:The aim of this study is to address the association between leukocytospermia and varicocele in patients with infertility. METHODS:We had revised the studies from 2000-2025 that addressed the role of each leukocytospermia, varicocele and both of them on infertility. RESULTS:Recent studies have suggested a potential link between leukocytospermia and varicocele, particularly in infertile patients, with each condition potentially exacerbating the detrimental effects of the other. CONCLUSION:This review had explored the independent and combined impacts of leukocytospermia and varicocele on semen parameters and hormonal profiles, shedding light on their roles in male infertility and underlining the importance of integrated diagnostic and therapeutic approaches.
Platelet-rich plasma (PRP) is an autologous regenerative therapy investigated for improving endometrial receptivity, ovarian function, and reproductive outcomes. To address inconsistent findings across existing reviews, we conducted an umbrella review of systematic reviews and meta-analyses identified from PubMed, Embase, Web of Science, and the Cochrane Library, with evidence appraised using AMSTAR-2 and GRADE. Twenty-one reviews were included. In women with recurrent implantation failure, intrauterine PRP was associated with improved live birth, clinical pregnancy, and biochemical pregnancy rates. Similar benefits were observed in women with previous implantation failure and in assisted reproductive technology (ART) populations. PRP also modestly increased endometrial thickness and implantation rates. In women with thin endometrium or intrauterine adhesions, PRP improved pregnancy outcomes and reduced cycle cancellation, while miscarriage rates were largely unchanged. Intra-ovarian PRP improved ovarian reserve markers, hormone profiles, oocyte yield, and embryo quality in women with poor ovarian response, premature ovarian insufficiency, or diminished ovarian reserve, although effects on pregnancy and live birth were variable. Overall, PRP shows potential benefits, but the certainty of evidence ranged from very low to moderate due to heterogeneity and methodological limitations. High-quality randomized controlled trials are required to confirm efficacy and guide clinical practice.
OBJECTIVE:Defective endometrial receptivity is an indispensable cause of infertility in endometriosis, yet the post-transcriptional regulatory mechanisms underlying this impairment remain poorly understood. The goal of this research was to describe how miR-29c-3p and its target, COL4A1, regulate endometrial epithelial cell function and embryo adhesion. METHODS:Endometrial epithelial cells were obtained from 14 women (including 7 with endometriosis and 7 controls) undergoing in vitro fertilization (IVF). Expression levels of miR-29c-3p and COL4A1 were quantified. Gain- and loss-of-function tests were employed in Ishikawa cells to assess cell adhesion capabilities and delineate downstream signaling pathways implicated in implantation. RESULTS:Women with endometriosis had considerably higher levels of miR-29c-3p expression in their endometrial epithelium. Mechanistically, increased expression of miR-29c-3p suppressed COL4A1, downregulated E-cadherin, and impaired JAr spheroid attachment. Notably, COL4A1 knockdown recapitulated these phenotypes by encouraging epithelial-mesenchymal transition (EMT), thereby compromising adhesive capacity. CONCLUSION:Our findings identify the miR-29c-3p/COL4A1/β-catenin axis as a pivotal hub controlling endometrial epithelial adhesion. In patients with endometriosis, this axis could be a potential molecular candidate to enhance fertility outcomes and restore endometrial receptivity.
PROBLEM:Maternal obesity and viral infection induce placental inflammation, but how their co-exposure influence fetoplacental development remains unclear. We hypothesised that maternal high fat (HF) diet and viral infection would independently induce placental inflammation and lipid peroxidation, reduce antioxidant defence, and cellular turnover. Further, HF diet would compromise placental capacity to adapt to infection. METHOD OF STUDY:Female C57BL/6J mice were fed a control (CON) or 62% HF diet six weeks before and throughout pregnancy and injected with poly(I:C) (viral mimic) or vehicle (VEH) 24 h before sacrifice at gestational days (GD) 12.5, 15.5, and 18.5 (n = 5-8/group/GD). Placental inflammasome (NLRP3), oxidative stress (4-HNE), antioxidant defence (GPx-4), and cellular proliferation-to-death ratio (Ki-67, Caspase-3) were assessed by immunohistochemistry, and mRNA expression of Tlr3, Irf3, Tlr4, Tirap, and Il-1β were measured by qPCR. Data were analysed by linear mixed models (p ≤ 0.05). RESULTS:At GD12.5, infection was associated with increased Tlr3 mRNA and immunoreactive (ir)-4-HNE, and reduced ir-GPx-4 expression in the placental labyrinth zone (LZ). By GD15.5, HF diet was associated with increased ir-NLRP3 in both LZ and junctional zones (JZ). Exposure to infection alone and co-exposure to HF diet and infection further increased LZ ir-NLRP3. At GD18.5, HF diet was associated with increased Tirap and Il-1β mRNA expression, ir-4-HNE in the JZ and ir-Caspase-3 in the LZ. CONCLUSIONS:Maternal HF diet and infection exert distinct effects on the placenta across gestation, suggesting that maternal overnutrition might reduce the placenta's capacity to handle adverse exposures, which may increase susceptibility to poor fetal outcomes.
PROBLEM:Endometriosis is a chronic, estrogen-dependent inflammatory disorder marked by ectopic endometrial-like tissue growth, resulting in pelvic pain, infertility, and significant declines in quality of life. Despite extensive research, current therapies remain largely symptomatic and are often associated with recurrence, hormonal adverse effects, and compromised fertility outcomes. Growing evidence indicates that oxidative stress, chronic inflammation, mitochondrial dysfunction, altered immune surveillance and metabolic dysregulation are central drivers of lesion establishment and progression. However, these interconnected mechanisms are often examined in isolation, limiting translational progress. METHOD OF STUDY:We provide a comprehensive, integrative analysis of the molecular and cellular pathways underlying endometriosis, with particular emphasis on oxidative stress-inflammation crosstalk, signalling cascades supporting lesion survival, and emerging metabolic and mitochondrial targets. By critically synthesising recent experimental, preclinical, and clinical findings, this review highlights mechanistic overlaps that may explain therapeutic resistance and disease recurrence. Furthermore, it evaluates novel pharmacological and nutraceutical interventions targeting redox imbalance, inflammatory mediators, and intracellular signalling pathways, thereby expanding the conceptual framework beyond conventional hormonal suppression. Rising global endometriosis prevalence and its socioeconomic burden necessitate a shift from purely symptomatic management to mechanism-driven therapeutic strategies. RESULTS:This review addresses that gap by consolidating dispersed evidence into a unified mechanistic perspective, identifying promising translational targets, and proposing future research directions. The insights provided will help in creating safer, fertility-preserving and more durable treatments. Thus, we categorise natural products by: (1) translational development stage (in vitro to clinical candidate); (2) regulatory pathway (dietary supplement, herbal medicine, or pharmaceutical); and (3) clinical context (e.g., pain control, recurrence prevention, or fertility preservation). CONCLUSION:This structured, clinically-oriented framework distinguishes the present synthesis from mechanistic reviews and serves to guide both future research design and rational integration of natural products into endometriosis therapeutic strategies.
Sex hormones and reproductive transitions profoundly shape immune, metabolic, neuropsychological, and mucosal biology, as well as HIV persistence, across women's lives. Although women constitute the majority of people with HIV worldwide, hormonal and reproductive biology are still not sufficiently incorporated into HIV cure research. Cisgender women, transgender women on gender-affirming hormone therapy (GAHT), and gender-diverse individuals assigned female at birth are underrepresented in cure studies, despite experiencing unique and changing hormonal states that influence estrogen signaling, tissue-specific hormone exposure, and immune function. Estradiol, progesterone, and hormone-based therapies, including contraception, GAHT, and menopausal hormone therapy, influence innate and adaptive immunity, inflammatory responses, epithelial barrier function, and cardiometabolic and neurocognitive pathways. These processes also shape tissue-specific HIV reservoir formation and maintenance, modulate proviral transcription, and affect immune effector functions. However, most HIV cure strategies have been developed without systematically considering these hormone-dependent mechanisms, which limits mechanistic understanding, broad applicability, and translational relevance. In this review, we synthesize emerging evidence at the intersection of reproductive endocrinology and HIV immunovirology, identify critical knowledge gaps, and propose priorities for life-course, hormone-informed HIV cure strategies. We argue that meaningful inclusion of women and gender-diverse individuals is essential not only for ethically grounded, equity-centered, community-engaged research practices but also for the scientific rigor needed to achieve durable ART-free virologic control and cure.
PROBLEM:Gestational diabetes mellitus (GDM) is a common metabolic complication of pregnancy associated with adverse maternal and fetal outcomes. Nevertheless, the molecular mechanism of placental dysfunction in GDM are still not clear, especially the role of ferroptosis and its interplay with oxidative stress, inflammation, and angiogenesis. METHOD OF STUDY:Placental tissues from GDM pregnancies were examined to assess oxidative stress, antioxidant defense, ferroptosis regulation, inflammatory signaling, and angiogenic pathways. Expression levels of key molecular markers were evaluated, and correlation analyses were performed to identify mechanistic interrelationships. RESULTS:GDM placenta demonstrated elevated oxidative stress markers, including P22PHOX and TXNIP, accompanied by reduced antioxidant markers, such as HO-1, NQO1, SOD2, and CAT, indicating impaired cellular defense. Ferroptosis regulation was disrupted, as anti-ferroptotic markers GPX4, SLC7A11, and NRF2 were significantly downregulated, while pro-ferroptotic markers TFR1 and ACSL4 were increased, suggesting enhanced iron accumulation and lipid peroxidation. This was accompanied by heightened inflammation, evidenced by increased IL-6, IL-1β, TNF-α, and NF-κB activation, alongside reduced IL-10 expression. Furthermore, angiogenesis was impaired, reflected by decreased VEGFA, HIF-1α, and SDF-1α levels, highlighting poor vascular development in the placenta. Additionally, Correlation analyses demonstrated strong associations between ferroptosis markers and oxidative stress, inflammatory, and angiogenic pathways, suggesting the possible presence of an interconnected regulatory network. CONCLUSIONS:These findings identify ferroptosis as a central regulator of GDM-associated placental dysfunction, through a possible interconnected network of oxidative stress, inflammation, and impaired angiogenesis. Targeting ferroptosis may offer a possible therapeutic option to restore placental function and improve maternal-fetal outcomes in GDM.
BACKGROUND:The cytokines interleukin (IL)-6 and transforming growth factor-beta (TGF-β) are established inducers of pathogenic T helper 17 (Th17) cells from naïve T cells. In the maternal-fetal compartment, IL-6 signaling elevates levels of indoleamine 2,3-dioxygenase 1 (IDO1). This study investigated whether IL-6 regulates Th17 cytokine production through IDO1. METHODS:Human decidua and chorionic villi (HDCV) were collected from normal early pregnant women undergoing elective termination. For HDCV culture, explants were treated with increasing doses of IL-6 (0-50 ng/mL) or co-treated with IL-6 and the IDO1 inhibitor 1-methyltryptophan (1-MT) for 24 h. HDCV were also treated with IL-6 (5 ng/mL) alone or in combination with TGF-β (0.01-0.1 ng/mL) for 24 h. Recurrent pregnancy loss (RPL) mice were intraperitoneally injected with IL-6 (2, 10, or 50 ng/mL), alone or combined with 1-MT and/or Cosentyx, from gestational day (GD) 0.5 to 8. Protein expression levels of IL-6, IDO1, IL-17, and IL-22 were assessed by Western blotting and immunohistochemistry. Embryo absorption rate (EAR) was calculated on GD 12.5. Cytokine concentrations in supernatants or serum were measured using enzyme-linked immunosorbent assay. RESULTS:In HDCV tissues, IL-6 positively correlated with IDO1 and negatively correlated with IL-17/IL-22. Exogenous IL-6 dose-dependently upregulated IDO1 and suppressed IL-17/IL-22 in cultured explants, effects reversed by 1-MT. Physiological TGF-β1 (0.01-0.1 ng/mL) enhanced IL-6-induced IDO1 upregulation and Th17 cytokine suppression. In RPL mice, IL-6 reduced EAR and placental IL-17/IL-22 expression while increasing IDO1; these effects were blocked by 1-MT and restored by Cosentyx. CONCLUSIONS:During normal pregnancy, IL-6 alone or the combination of IL-6 and TGF-β at the maternal-fetal interface may inhibit Th17 cytokine production by upregulating IDO1 expression, thereby maintaining pregnancy stability.
PROBLEM:Preeclampsia (PE) is a serious human pregnancy complication and remains the most complex hypertensive disorder due to its multifactorial nature and multisystemic effects. Despite the incomplete understanding of the PE pathophysiology, it is well-accepted that placental changes in PE are associated with oxidative stress, increasing the excessive production of cytokines and other inflammatory mediators. Thus, agents such as silibinin, a non-toxic natural polyphenolic flavonoid with antioxidant, anti-inflammatory, and hepatoprotective properties could modulate this profile for better disease resolution. This study aimed to investigate the effect of silibinin treatment on Nω-nitro-L-arginine methyl ester (L-NAME)-induced PE in rats, exploring its potential as a preventive anti-inflammatory agent. METHODS OF STUDY:Pregnant Wistar rats were treated or not during gestation (days 10-19) with L-NAME (70-80 mg/kg/day) in drinking water and with silibinin (100 mg/kg/day, orally) starting on days 0, 7 or 14 of pregnancy. Systolic blood pressure was recorded on gestation days 0 and 20. The rats were euthanized on day 20. Then, we evaluated proteinuria, maternal weight gain, and litter weight. Tumor necrosis factor- alpha (TNF-α), interleukin-1 (IL-1β), IL-6, IL-10, interferon-gamma (IFN-γ), heat shock protein 70 (Hsp70) and NF-κB activity were determined in liver and placenta homogenates. RESULTS:Our findings indicated that silibinin treatment decreased the production of the inflammatory cytokines TNF-α, IL-1β, IFN-γ, and reduced Hsp70 levels in the placenta and liver homogenate. NF-κB activation was also decreased in these organs of silibinin-treated groups, especially in the LN+SB0 and LN+SB7 groups. CONCLUSION:This study introduces a novel use of silibinin as a preventive agent in a PE-like model that reproduces essential features of human PE, providing physiological relevance to the findings. Overall, our data emphasize the translational potential of silibinin for PE prevention, showing promising effects on key inflammatory and stress-related pathways.
PROBLEM:An association between periodontal disease and adverse pregnancy outcomes, with high risk for the mother and the newborn, has been widely documented. So far, the mechanisms linking gingival inflammation to placental dysfunction remain poorly defined. METHODS OF STUDY:In this study, we aimed to investigate whether bioactive inflammatory components in the gingival crevicular fluid are capable of modulating placental and immune cells in vitro and to analyse whether these effects correlate with periodontal parameters. We conducted a cross-sectional study in 37 pregnant women undergoing caesarean section, evaluating their gingival inflammatory condition and collecting gingival crevicular fluid (GCF) within 24 h of delivery. GCF samples were assayed on placental explants, vascular endothelial cells, and neutrophils in vitro to determine inflammatory and functional profiles. RESULTS:The GCF from pregnant women induced a proinflammatory response in placental tissue and an antiangiogenic effect on endothelial cells. Neutrophils exposed to the GCF samples of pregnant women showed increased production of reactive oxygen species and neutrophil extracellular trap (NET) formation. The extent of the inflammatory response correlated with the degree of the maternal gingival inflammatory condition. CONCLUSION:These findings suggest that components present in the GCF induce inflammatory stress even in normal pregnancies. Their potential contribution to periodontal disease-associated complications requires further studies. The present work highlights the value of integrating oral health into prenatal care and offers new experimental approaches to monitor systemic effects of periodontal disease during pregnancy. TRAIL REGISTRATION:This was an observational human study and was not registered in a public clinical trial/study registry.
