Search Results (94)

Diabetes is increasingly recognized as a chronic inflammatory disease marked by systemic metabolic disturbances, with endothelial dysfunction playing a central role in its complications. Hyperglycemia, a hallmark of diabetes, drives endothelial damage by inducing excessive reactive oxygen species (ROS) production, particularly hydrogen peroxide (H₂O₂). This oxidative stress impairs endothelial cells, which are vital for vascular health, leading to severe complications such as diabetic nephropathy, retinopathy, and coronary artery disease—major causes of morbidity and mortality in diabetic patients. Recent studies have highlighted the therapeutic potential of placenta-derived mesenchymal stem cells (pMSCs), in mitigating these complications. pMSCs exhibit anti-inflammatory, antioxidant, and tissue-repair properties, showing promise in reversing endothelial damage in laboratory settings. To explore their efficacy in a more physiologically relevant context, we used a streptozotocin (STZ)-induced diabetic mouse model, which mimics type 1 diabetes by destroying pancreatic beta cells and causing hyperglycemia. pMSCs were administered via intra-peritoneal injections, and their effects on endothelial injury and tissue damage were assessed. Metabolic tests, including glucose tolerance tests (GTTs) and insulin tolerance tests (ITTs) revealed that pMSCs did not restore metabolic homeostasis or improve glucose regulation. However, histopathological kidney, heart, and eye tissue analyses demonstrated significant protective effects. pMSCs preserved glomerular structure in the kidneys, protected cardiac blood vessels, and maintained retinal integrity, suggesting their potential to address diabetes-related tissue injuries. Although these findings underscore the therapeutic potential of pMSCs for diabetic complications, further research is needed to optimize dosing, elucidate molecular mechanisms, and evaluate long-term safety and efficacy. Combining pMSCs with other therapies may enhance their benefits, paving the way for future clinical applications. Full article

Background: Iron is an important micronutrient under physiological conditions, including pregnancy. On the other hand, excessive iron intake is also associated with adverse pregnancy outcomes. Macrophages are crucial in regulating iron homeostasis and pregnancy conditions. However, the role of macrophages in iron metabolism during pregnancy is unclear. Therefore, we used mouse models to investigate whether maternal iron overload induces pregnancy complications and their interactions with macrophages. Methods and Results: Administration of high-dose iron (iron dextran) by intraperitoneal injection to pregnant mice induced pregnancy complications such as fetal death, but low-dose iron did not affect fetal weight. In the placenta, the amount of iron was significantly increased and levels of macrophages were decreased by iron administration. In the liver, iron administration dramatically increased the amount of iron, with increased inflammatory cytokines tumor necrosis factor-α (TNFα) and interleukin-6. Macrophages were observed to surround deposited iron in the liver. In an in vitro experiment, treatment with iron stimulated TNFα secretion with cell death in macrophages, but not in liver cells. To investigate the importance of macrophages during pregnancy, clodronate liposomes were administered to reduce macrophages in pregnant mice. The macrophage reduction in pregnant mice resulted in an increased absorption rate and fetal growth restriction, together with higher iron accumulation and inflammatory cytokines in the liver. Conclusions: Maternal excess iron may induce inflammatory conditions with macrophage dysfunction in the liver, resulting in pregnancy complications. The reduction in macrophages also induced higher iron levels and adverse effects during pregnancy, suggesting a vicious cycle between excessive iron and macrophage dysfunction during pregnancy. Full article

Background/Objectives: Acetaminophen (APAP) is a widely used analgesic and antipyretic, but overdose can lead to APAP-induced liver injury (AILI), a major cause of acute liver failure. While N-acetylcysteine (NAC) is the current standard of care, its efficacy is significantly reduced when administered after the peak time of liver injury, highlighting the need for alternative therapeutic strategies. Human placenta hydrolysate (HPH) has shown potential as a therapeutic agent for various liver diseases due to its rich content of bioactive compounds. This study aimed to investigate the hepatoprotective effects of HPH in a mouse model of AILI. Methods: HPH was administered to mice for three days prior to APAP treatment. The effects of HPH on liver morphology, necrosis, liver enzymes, phase I/II detoxification enzymes, oxidative stress markers, and inflammatory cytokines were evaluated. Results: HPH pretreatment attenuated APAP-induced liver necrosis and congestion, reduced serum levels of liver enzymes. In addition, HPH showed a concentration-dependent attenuation of APAP-induced decrease in human hepatocyte viability. HPH modulated phase I/II enzyme expression by downregulating CYP2E1 and upregulating SULT1A1, UGT1A6, GSTP1, and TPMT. HPH also exhibited antioxidant effects by increasing SOD and GPx activities, reducing MDA levels, and restoring the GSH/GSSG ratio. Furthermore, HPH attenuated the APAP-induced increase in the inflammatory cytokines TNF-α and IL-6. These findings suggest that HPH protects against AILI through multiple mechanisms, including the modulation of phase I/II detoxification, activation of antioxidants, and inhibition of inflammation. Conclusions: HPH could be a potential therapeutic option for APAP overdose and related liver injuries. Full article

Acute radiation syndrome (ARS) results from high-dose ionizing radiation (IR) exposure, with bone marrow (BM) being highly susceptible due to its proliferative activity. BM injury causes pancytopenia, leading to infections, anemia, and bleeding. Mesenchymal stem cells (MSCs) hold promise for ARS treatment because of their immunomodulatory, anti-inflammatory, and regenerative properties. However, challenges such as replicative senescence, poor survival, and engraftment in irradiated microenvironments limit their efficacy. This study evaluated rapamycin-preconditioned placenta-derived MSCs (rPD-MSCs) in a mouse ARS model. Rapamycin was selected for preconditioning due to its ability to induce autophagy and modulate cytokine secretion. We assessed rapamycin-dependent modulation of autophagy-related genes and proteins, as well as hematopoietic cytokines secretion in PD-MSCs, and evaluated morphological changes in blood and BM at 7 and 21 days post-irradiation in ICR/CD1 mice. Preconditioning with rapamycin alters the secretion of granulocyte colony-stimulating factor (G-CSF), stem cell factor (SCF), and Fms-related tyrosine kinase 3 ligand (Flt3LG) in PD-MSCs without affecting cell viability. rPD-MSCs better enhance hematopoietic recovery, restore bone marrow cellularity, and increase peripheral blood cell counts by elevating the secretion of hematopoietic cytokines compared to non-preconditioned cells. These results highlight rapamycin preconditioning as a promising strategy to enhance MSCs therapeutic potential for ARS, supporting further preclinical and clinical exploration. Full article

Background: Preeclampsia is a leading cause of maternal and fetal morbidity and mortality, with obesity recognised as a significant risk factor. However, the direct contribution of obesity to the pathophysiology underpinning preeclampsia remains unclear. Objectives: This study aimed to develop and characterise a diet-induced obese mouse model with superimposed preeclampsia to better understand the impact of obesity on disease pathogenesis. Methods: Female mice were fed either standard rodent chow or a high-fat diet from weaning. At 8 weeks of age, mice were mated. Pregnant mice were treated with L-N^G-Nitro arginine methyl ester (L-NAME; to block nitric oxide production) from gestational day (D)7.5 to D17.5 to induce a preeclampsia-like phenotype. Blood pressure was measured on D14.5 and D17.5, followed by the collection of maternal and fetal tissues for histological, biochemical, and molecular analyses. Results: Obese dams exhibited significantly increased body, fat pad, and liver weights compared to lean controls. While L-NAME induced hypertension in the control mice, contrary to expectations, the L-NAME-induced hypertension was partially attenuated in obese dams, with significantly lower systolic and diastolic blood pressures at D14.5 and reduced systolic pressure at D17.5. Fetal weights were comparable between groups, however, placentas were significantly heavier with obesity. Endothelial function, inflammatory markers, and renal gene expression patterns suggested distinct physiological adaptations in obese preeclamptic-like mice. Conclusions: These findings challenge the prevailing assumption that obesity drives hypertension, endothelial dysfunction, and inflammatory markers. The differential vascular and physiological responses observed in the obese dams highlight the complexity of obesity–preeclampsia interactions and underscore the need for refined preclinical models to disentangle mechanistic contributions. This work has implications for personalised management strategies and targeted therapeutic interventions in obese pregnancies at risk of preeclampsia. Full article

Nanoplastics (NPs) represent a major challenge in environmental contamination resulting from the physical, chemical, and biological degradation of plastics. Their characterization requires advanced and expensive methods, which limit routine analyses. The biological effects of NPs depend on their chemical and physical properties, which influence toxicity and interactions with biological systems. Studies in animal models, such as Daphnia magna and Danio rerio, show that NPs induce oxidative stress, inflammation, DNA damage, and metabolic alterations, often related to charge and particle size. NPs affect endocrine functions by acting as endocrine disruptors, interfering with thyroid and sex hormones and showing potential transgenerational effects through epigenetic modifications, including DNA hyper- and hypomethylation. Behavioral and neurofunctional alterations have been observed in Danio rerio and mouse models, suggesting a link between NP exposure and neurotransmitters such as dopamine and serotonin. Despite limited human studies, the presence of NPs in breast milk and placenta underscores the need for further investigation of health effects. Research focusing on genetic and epigenetic markers is encouraged to elucidate the molecular mechanisms and potential risks associated with chronic exposure. Full article

Major histocompatibility complex class I (MHC-I) gene expression in the placenta is modulated to tailor the maternal immune response to fetal antigens during pregnancy. This study evaluated MHC-I expression through immunohistochemistry (IHC) using an anti-mouse preimplantation embryo development (PED) clone Qa-2 and anti-bovine leukocyte antigen I (BoLA) monoclonal antibody clone IL-A88 (n = 23), as well as RT-qPCR (n = 17) for classical and non-classical (BoLA-NC) genes in control and cloned bovine placentomes during early and near-term gestation. Control samples showed minimal Qa-2 protein expression in early gestation, with intense labeling in trophoblasts and the maternal uterine epithelium near term. In contrast, cloned samples exhibited intense Qa-2 labeling in both maternal and trophoblastic epithelia at both stages, while trophoblast giant cells (TGCs), located apposed to the maternal epithelium, showed no labeling. Control samples exhibited intense IL-A88 labeling in the maternal epithelium at both stages. In cloned samples, weak to no labeling was observed in early gestation, with intense labeling in maternal and fetal epithelium near term. RT-qPCR revealed significant upregulation of BoLA-NC3 in early gestation, with sustained elevated expression in cloned samples in the near term. These findings suggest that altered BoLA protein expression and gene regulation in cloned pregnancies may contribute to pregnancy complications and increased losses. Full article

PDRN, polydeoxyribonucleotide, which is used as a tissue-regeneration material, is present in human cells under physiological conditions and stimulates regeneration and metabolic activity. PDRN can be used as a biomaterial for several types of regeneration, including wound healing, to promote cell growth and growth-factor production. The aims of this study were to determine the effect of PDRN derived from human placenta-derived mesenchymal stem cells (hPD-MSCs) on cellular regeneration through A2A receptor signaling and to investigate its therapeutic effects in a mouse model of wound healing. Human PDRN (UNIPlax) was extracted from hPD-MSCs fragmented via a sonication system and evaluated for its effect on the migration of HaCaT cells in an in vitro system and in a wound-healing mouse model in vivo. Compared with the sham treatment, UNIPlax treatment significantly increased the migration of injured HaCaT cells (p < 0.05). Additionally, the tube formation of human umbilical vein endothelial cells (HUVECs) was greater than that of the sham group (p < 0.05), and the effects of this treatment were mediated through the A2A receptor. Furthermore, UNIPlax treatment led to a decrease in wound size; in addition, the area of granulation and the rate of collagen formation at the wound site were significantly greater than those in the sham group in the wound-healing mouse model (p < 0.001). We also confirmed that UNIPlax promoted tissue regeneration and the expression of VEGF through the A2A receptor. Taken together, these findings indicate that UNIPlax has potential for regeneration of damaged tissues, including during wound healing. Full article

A eutopic endometrium in endometriosis shows altered immune responses, including abnormalities of NK cells and expression of plasma cells, related to reproductive issues. This study investigated the counts of CD56-positive NK cells and CD138-positive plasma cells in the basal decidua of term placentas in singleton pregnancies after endometriosis-related infertility conceived by assisted reproductive technology (ART). This single-center, case-control study involved immunohistochemical analysis of CD56-positive NK cells and CD138-positive plasma cells in basal decidua using primary monoclonal mouse antibodies, followed by secondary antibodies using a standardized protocol. CD56 and CD138 immunohistochemically positive cells were reported as the total cell count for each studied antibody expressed per 1 mm² of basal decidua (Olympus BX46 and Olympus Image Analyzer). Placental samples containing basal decidua from 36 participants with endometriosis-related infertility who conceived by ART, 31 participants with male factor infertility who conceived by ART and 40 healthy controls were included. Endometriosis decidua showed the lowest median count of CD56-positive NK cells (11.5 / mm², p = 0.039) in BD compared to male factor group (25 / mm²) and healthy controls (24.5 / mm²). No differences were found for CD138-positive plasma cells counts between study groups. Basal decidua in pregnancies after endometriosis-related infertility showed reduced total count of CD56-positive NK cells, without differences in the CD138-positive plasma cell counts compared to control groups. Future studies should investigate how changes in NK cells throughout pregnancy affect the development of perinatal complications and placental pathologies in women with endometriosis, which could uncover potential diagnostic and therapeutic targets. Full article

Available evidence from animal studies suggests that placental serotonin plays an important role in proper fetal development and programming by altering brain circuit formation, which later translates into altered abnormal adult behaviors. Several environmental stimuli, including stress and maternal inflammation, affect placental and, hence, fetal serotonin levels and thus may disturb fetal brain development. We investigated the effect of prenatal stress of varying intensities on the formation of adaptive behaviors in mouse offspring and the role of placental serotonin in these processes. Mild prenatal stress increased placental serotonin synthesis, whereas exposure to moderate stress decreased it. Prenatal stress of varying intensities also resulted in multidirectional changes in animal behavior in progeny, consistent with changes in serotonin levels in the placenta and fetal tissues. Mice exposed to mild prenatal stress showed higher sociality and exploratory activity, whereas, after moderate stress, in contrast, they avoided contact with other individuals of their species and had reduced exploratory activity, with no effect on locomotor activity. Thus, in mice, stressors of varying intensities during the critical period of intrauterine development can affect the synthesis of serotonin by the placenta and lead to multidirectional changes in animal behavior in postnatal life. Full article

When postmenopausal women are under stress conditions, this exacerbates mood disorders and issues with neuroimmune systems. The porcine placenta is known to relieve menopausal depression in clinical trials, but its underlying mechanisms for depression and anti-inflammatory functions remain poorly defined. The present study was designed to examine the anti-inflammatory effects of enzymatic porcine placenta hydrolysate (EPPH) on LPS-induced levels of nitric oxide (NO), prostaglandin E2 (PGE2), corticosterone (CORT), and pro-inflammatory cytokine interleukin-1 beta (IL-1β) in RAW 264.7 macrophage cells. In addition, the neurite outgrowth of PC12 cells was evaluated to examine the effects of EPPH on neurite growth. To mimic the symptoms of women with menopause-related depression, a stressed ovariectomized (OVX) female mouse model was used to evaluate the antidepressant effects of EPPH. The female mice were randomly divided into five groups: (1) the sham-operated (Sham) group, (2) the OVX + repeated stress + saline-treated (OVX + ST) group, (3) the OVX + repeated stress + estradiol (0.2 mg/kg)-treated (positive control) group, (4) the OVX + repeated stress + EPPH (300 mg/kg)-treated (300) group, and (5) the OVX + repeated stress + EPPH (1500 mg/kg)-treated (1500) group. Female mice were OVX and repeatedly immobilization-stressed for 2 weeks (2 h/day). A tail suspension test was conducted on the 13th day, followed by the forced swimming test on the 14th day to assess the antidepressant effects of EPPH. After the behavioral tests, the levels of CORT, PGE2, and IL-1β were evaluated. In addition, c-Fos expression in the paraventricular nucleus (PVN) was evaluated using immunohistochemistry. The concentrations of NO, PGE2, and IL-1β stimulated by LPS were significantly reduced via the addition of EPPH to RAW 264.7 cells. EPPH significantly promoted neurite outgrowth in PC12 cells compared to that of the controls. In the tail suspension test, the duration of immobility was reduced in mice treated with EPPH 1500 compared to the OVX + ST group. The EPPH 1500 group had significantly decreased levels of c-Fos-positive neurons in the PVN and reduced levels of CORT and IL-1β in the serum of the Sham group. These results suggested that the high dose of EPPH administration induced the antidepressant-like effect in the ovariectomized mice with repeated stress via downregulating the levels of CORT, IL-1β, and PGE2 in the serum through reducing the expression of c-Fos in the PVN regions. Full article

Exposure to cigarette smoke is known to induce disease during pregnancy. Recent evidence showed that exposure to secondhand smoke (SHS) negatively impacts fetal and placental weights, leading to the development of intrauterine growth restriction (IUGR). Electronic cigarettes (eCigs) represent a phenomenon that has recently emerged, and their use is also steadily rising. Even so, the effects of SHS or eCigs during gestation remain limited. In the present study, we wanted to characterize the effects of SHS or eCig exposure at two different important gestational points during mouse pregnancy. C57/Bl6 mice were exposed to SHS or eCigs via a nose-only delivery system for 4 days (from 14.5 to 17.5 gestational days (dGA) or for 6 days (from 12.5 dGA to 17.5 dGA)). At the time of necropsy (18.5 dGA), placental and fetal weights were recorded, maternal blood pressure was determined, and a dipstick test to measure proteinuria was performed. Placental tissues were collected, and inflammatory molecules in the placenta were identified. Treatment with SHS showed the following: (1) a significant decrease in placental and fetal weights following four days of exposure, (2) higher systolic and diastolic blood pressure following six days of exposure, and (3) increased proteinuria after six days of exposure. Treatment with eCigs showed the following: (1) a significant decrease in placental weight and fetal weight following four or six days of exposure, (2) higher systolic and diastolic blood pressure following six days of exposure, and (3) increased proteinuria after six days of exposure. We also observed different inflammatory markers associated with the development of IUGR or PE. We conclude that the detrimental effects of SHS or eCig treatment coincide with the length of maternal exposure. These results could be beneficial in understanding the long-term effects of SHS or eCig exposure in the development of placental diseases. Full article

Brucellosis is one of the most common and widespread bacterial zoonoses and is caused by Gram-negative bacteria belonging to the genus Brucella. These organisms are able to infect and replicate within the placenta, resulting in abortion, one of the main clinical signs of brucellosis. Although the mouse model is widely used to study Brucella virulence and, more recently, to evaluate the protection of new vaccines, there is no clear consensus on the experimental conditions (e.g., mouse strains, doses, routes of inoculation, infection/pregnancy time) and the natural host reproducibility of the pregnant mouse model for reproductive brucellosis. This lack of consensus calls for a review that integrates the major findings regarding the effect of Brucella wild-type and vaccine strains infections on mouse pregnancy. We found sufficient evidence on the utility of the pregnant mouse model to study Brucella-induced placentitis and abortion and propose suitable experimental conditions (dose, time of infection) and pregnancy outcome readouts for B. abortus and B. melitensis studies. Finally, we discuss the utility and limitations of the pregnant mouse as a predictive model for the abortifacient effect of live Brucella vaccines. Full article

The etiopathogenesis of preeclampsia, a leading hypertensive disorder of pregnancy, has been proposed to involve an abnormal circulating sex hormone profile and misexpression of placental estrogen and progesterone receptors (ER and PR, respectively). However, existing research is vastly confined to third trimester preeclamptic placentas. Consequently, the placental–uterine molecular crosstalk and the dynamic ER and PR expression pattern in the peri-conception period remain overlooked. Herein, our goal was to use the BPH/5 mouse to elucidate pre-pregnancy and early gestation Er and Pr dynamics in a preeclamptic-like uterus. BPH/5 females display low circulating estrogen concentration during proestrus, followed by early gestation hypoestrogenemia, hyperprogesteronemia, and a spontaneous preeclamptic-like phenotype. Preceding pregnancy, the gene encoding Er alpha (Erα, Esr1) is upregulated in the diestrual BPH/5 uterus. At the peak of decidualization, Esr1, Er beta (Erβ, Esr2), and Pr isoform B (Pr-B) were upregulated in the BPH/5 maternal–fetal interface. At the protein level, BPH/5 females display higher percentage of decidual cells with nuclear Erα expression, as well as Pr downregulation in the decidua, luminal and glandular epithelium. In conclusion, we provide evidence of disrupted sex hormone signaling in the peri-conception period of preeclamptic-like pregnancies, potentially shedding some light onto the intricate role of sex hormone signaling at unexplored timepoints of human preeclampsia. Full article

Preeclampsia (PE) is characterized by maternal hypertension and placental dysfunction, often leading to fetal growth restriction (FGR). It is associated with an overexpression of the anti-angiogenic sFLT1 protein, which originates from the placenta and serves as a clinical biomarker to predict PE. To analyze the impact of sFLT1 on placental function and fetal growth, we generated transgenic mice with placenta-specific human sFLT1 (hsFLT1) overexpression. Immunohistochemical, morphometrical, and molecular analyses of the placentas on 14.5 dpc and 18.5 dpc were performed with a focus on angiogenesis, nutrient transport, and inflammation. Additionally, fetal development upon placental hsFLT1 overexpression was investigated. Dams exhibited a mild increase in serum hsFLT1 levels upon placental hsFLT1 expression and revealed growth restriction of the fetuses in a sex-specific manner. Male FGR fetuses expressed higher amounts of placental hsFLT1 mRNA compared to females. FGR placentas displayed an altered morphology, hallmarked by an increase in the spongiotrophoblast layer and changes in labyrinthine vascularization. Further, FGR placentas showed a significant reduction in placental glycogen storage and nutrient transporter expression. Moreover, signs of hypoxia and inflammation were observed in FGR placentas. The transgenic spongiotrophoblast-specific hsFLT1 mouse line demonstrates that low hsFLT1 serum levels are sufficient to induce significant alterations in fetal and placental development in a sex-specific manner. Full article