Despite corrective surgery, patients with congenital heart disease (CHD) have residual regions of disturbed oscillatory blood flow which can induce upregulation of proinflammatory cytokines and adhesion molecules. Data on cytokine and cellular adhesion molecule (CAM) profiles in low risk pregnancy and pregnancy complicated by CHD are limited. The objective of this work was to study the profile of IL-6, IL-10, TNFα, ghrelin, GROα, and ICAM/VCAM in pregnancy in women with and without CHD and test the hypothesis that the circulating levels of these are correlated with obstetric outcomes.

Prospective study of women ≥18 years carrying a singleton low risk pregnancy low-risk (LR-group) and pregnant women with CHD (CHD-group). Study visits were conducted between 10 and 14, 18-22 and 30-34 weeks' gestation with blood sampling for immune profiling using the Bio-Plex® Multiplex Immunoassay. The immune profile was investigated in both groups and correlated with obstetric outcomes. This study was approved by the Health Research Authority and the London South East Research Ethics Committee (REC reference: 17/LO/0970).

Forty-five samples in 30 participants with CHD and 45 gestational age-matched samples from 34 low-risk pregnant women were analysed. Women in the CHD-group delivered earlier (38 + 6 weeks vs 39 + 4 weeks, p = 0.005) and had smaller babies (2940 g, 30.0 centile vs 3415 g, 63.5 centile, p < 0.001). There were no significant differences in the levels of IL-6, IL-10 or TNFαin both groups across trimesters. Levels of GROα increased in both groups but less so in the CHD group. Levels of ghrelin decreased in both groups but less so in the CHD group. Levels of ICAM decreased as pregnancy progressed in the CHD group. Levels of VCAM increased in both groups but more significantly in the CHD-group (second trimester, p < 0.001; third trimester, p = 0.045). Women in the CHD-group had higher levels if IL-6 (p = 0.005) and ICAM (p < 0.001) lower levels of IL-10 in the third trimester (p = 0.018). There was a significant positive association between levels of IL-6 in the first trimester and birthweight centiles (rs = 1.00, p < 0.001) in the CHD group.

There was minimal fluctuation in the levels of the studies cytokines during pregnancy with exception of GROα and ghrelin, both implicated in fetal growth. Women with CHD had higher levels of proinflammatory cytokines and ICAM in the first trimester, and lower levels of IL-10 in the third trimester, suggesting a more proinflammatory state. High levels of VCAM in the CHD group could be secondary to endothelial activation.

This study aims to investigate the role of CEACAM1 in preterm birth. Preterm birth is a phenomenon with numerous triggers, with the immune system hypothesized to play a significant role in the process, aligning with the concept of 'birth as an immunological rejection phenomenon'. There are several approaches to predict preterm birth, and the determination of sCEACAM1 levels, a member of the carcinoembryonic antigen family, may serve as a potential candidate biomarker.

A single-center prospective case series study included 67 pregnant women aged 18 years or older who presented before 37 weeks of gestation with signs of preterm birth in the years 2021-2023. At the time of admission, CEACAM1 was determined in maternal blood.

The median sCEACAM1 levels were significantly higher in women who delivered preterm compared to those who delivered at term respectively, 5014 pg/ml (IQR: 3592-8826) vs. 3353 pg/ml (IQR: 2354-5049) (p = 0.016). The median sCEACAM1 level in the group with PPROM (premature preterm rupture of membranes) at 34 weeks' gestation was 7001 pg/ml (IQR: 5683-13509), while the median sCEACAM1 level in the group without PPROM at 34 weeks' gestation was 3884 pg/ml (IQR; 2461-4985) (p < 0.001).

Pregnant women with preterm birth and/or PPROM before 34 weeks' gestation have higher CEACAM1 levels compared to women with threatened preterm labor who finally had labot at term. The results suggest early activated immune system as a potential pathomechanism of preterm delivery.

Calcium signaling is essential for immune function, myometrial contractions, and hormone secretion, all of which contribute to preterm birth. In this study, we investigated the associations of 3 single-nucleotide polymorphisms (SNPs) in CACNA1D gene, which encodes the Cav1.3 calcium channel, with the risk of spontaneous preterm birth (sPTB).

A hospital-based case-control study was conducted with 112 women of sPTB and 1120 term control women. Three CACNA1D SNPs (rs9810888 T/G, rs1045958 C/T, and rs881883 G/A) were genotyped.

The T/G genotype of the CACNA1D rs9810888 SNP was associated with a reduced risk of sPTB (odds ratio: 0.61, 95 % confidence interval: 0.41-0.91, P = 0.01, Pc = 0.03). However, no significant associations were observed for the other 2 SNPs. Haplotype analysis revealed no significant differences between the case and control groups.

Our findings suggest that the intronic rs9810888 T/G variant of CACNA1D gene protects against sPTB in Taiwanese women.

In vitro human liver models are indispensable for compound metabolism/toxicity screening, disease modeling, and regenerative medicine. While induced pluripotent stem cell-derived human hepatocyte-like cells (iHeps) mitigate the sourcing limitations with primary human hepatocytes (PHHs), their functional maturity is rate-limiting for application use. During development, immature hepatoblasts interact with different non-parenchymal cell (NPC) types, such as mesenchyme and endothelia, in a spatiotemporal manner to progress through functional maturation. Modeling such interactions in vitro is critical to elucidate the key regulators of iHep maturation. Here, we utilized high-throughput droplet microfluidics to encapsulate iHeps within monodisperse collagen I microgels (Ø ∼ 250 µm), which were coated with NPCs to generate 'microtissues' placed within microwells in multiwell plates. Embryonic fibroblasts and liver sinusoidal endothelial cells (LSECs) induced the highest level of iHep maturation over 4+ weeks of culture compared to adult hepatic stellate cells (myofibroblastic), liver portal fibroblasts, dermal fibroblasts, and human umbilical vein endothelial cells. Combining iHep microtissues in plates with Transwell inserts containing different NPC types enabled the modeling of dynamic heterotypic signaling on iHep maturation; introducing embryonic fibroblast signaling first, followed by LSECs, led to the highest iHep maturation. Unique cytokine secretion profiles were detected across the top-performing microtissue configurations; stromal-derived factor-1 alpha was validated as one factor that enhanced iHep maturation. Lastly, gene expression patterns and regulatory networks showed adult PHH-like maturation in LSEC/iHep microtissues compared to iHep-only microtissues. Overall, microtissues are useful for elucidating the microenvironmental determinants of iHep maturation and for future use in downstream applications. STATEMENT OF SIGNIFICANCE: Induced pluripotent stem cell-derived hepatocyte-like cells (iHeps) hold great promise for drug screening, disease modeling, and regenerative medicine but often exhibit immature phenotypes. We utilized high-throughput droplet microfluidics to generate 3D microtissues containing iHeps and non-parenchymal cell (NPC) types to elucidate the effects of dynamic NPC signaling on iHep maturation. We observed that iHep maturation is significantly enhanced with embryonic fibroblasts and liver sinusoidal endothelial cells (LSEC) compared to adult liver fibroblasts and non-liver endothelia; the LSEC/iHep microtissues showed adult liver-like gene expression signatures. The highest iHep maturation in microtissues was achieved when mesenchymal stimulation was introduced first, followed by LSEC stimulation. Our platform provides a robust framework to elucidate cellular and molecular mediators of iHep maturation and biomedical applications.

To further evaluate the effects of lymphocyte immunotherapy (LIT) for the treatment of RPL patients this study aimed to utilize this type of treatment in RPL patients with positive antinuclear antibodies (ANA) in comparison to ANA-negative RPL women. To this aim, 84 ANA-positive, 114 ANA negative, and 50 healthy pregnant women were recruited. To examine the frequency of cells before and after LIT, flowcytometry technique was employed. The levels of cytokines gene expression were also measured using real-time PCR. The ELISA technique was employed to assess the level of secreted cytokines in serum. Initial evaluation before LIT showed significantly lower NK cells and Th1/Th2 ratio in healthy pregnant women compared to both ANA-negative, and positive patients. Moreover, healthy pregnant women had significantly lower pro-inflammatory cytokine (IFN-γ) and higher anti-inflammatory cytokines (TGF-β and IL-4) compared to RPL patients. After LIT, NK cells frequency significantly decreased in both ANA-negative and -positive groups, however, reduced Th1/Th2 ratio was only significant in ANA-negative group. Significantly increased and decreased IL-4 and IFN-γ were only observed in ANA-negative patients. Furthermore, patients receiving routine treatment did not experience any remarkable changes in terms of cell frequency and cytokine levels. This study showed a significant improvement in pregnancy outcomes including increased pregnancy rate and live birth, and decreased miscarriages in both ANA-negative and positive RPL patients, which were notably higher in ANA-negative group.

There have been remarkable advancements in understanding the complex and dynamic immune biological processes engaged during all stages of pregnancy. Exquisite control of immune processes is critical to successful outcome in all stages of pregnancy from ovulation to birth. There are many immunomodulatory therapeutics that may offer beneficial treatment options for a variety of diseases (e.g., inflammation/autoimmunity, cancer) to patients that are or desire to become pregnant. It is important to understand the potential for these immunomodulatory therapeutics to alter the critical immune processes in pregnancy to inform clinical risk relative to successful pregnancy. The Health and Environmental Sciences Institute-Developmental and Reproductive Toxicology/Immuno-safety Technical Committee (HESI DART/ITC) conducted a survey on approaches to assess adverse pregnancy outcomes with immunomodulators. HESI DART/ITC also organized a workshop for an extended discussion on immune mechanisms during pregnancy, the adequacy of current tools/methodologies to identify concerns for potential pregnancy hazards from immunomodulatory therapies, ways to identify and address scientific gaps, and global regulatory considerations across various immunomodulatory modalities and indications. In this manuscript we summarize learnings from these efforts to characterize risk within this patient population, promote more informed treatment decisions, and enable safer pharmacological interventions during pregnancy.

Discrete subaortic stenosis (DSS) is a congenital heart disease characterized by a narrowing of the passage below the aortic valve in the left ventricular outflow tract (LVOT) [1]. While endocardial endothelial cells (EECs) are known to play a role in DSS, the response of these cells to shear stress is not known. In this study, we hypothesize that the response of EECs to shear stress in the LVOT is a mediator of DSS.

To test this hypothesis, we conditioned porcine EECs to controlled shear stress regimes using cone and plate bioreactors. Subsequently, we quantified the concentration of proinflammatory cytokine in the conditioned media using the Luminex assay. Bulk-RNA sequencing was used to quantify changes in the genotype of the shear stress conditioned EECs.

The expression of CD31 was knocked down and subsequently, the changes in release of shear stress induced proinflammatory cytokines released by EECs quantified using the Luminex assay. The results of these studies show that the inflammatory cytokines were highly selected in the conditioning medium, and under bioreactor treatment the cell activated the PI3K-AKT and TNF-a signaling, which also triggered the other immune cell responses though Th1, Th2 and Th17 cell differentiation pathways. Furthermore, CD31 was identified as a mediator of the pro-inflammatory response of shear stress conditioned EECs.

The studies provide a clear link between shear stress, and the subsequent proinflammatory response of EECs as a mediator of DSS.

Based on an exhaustive review, a theory was proposed with an immunoendocrine perspective on the reactivation of dormant Toxocara canis larvae in pregnant bitches and their transmission to fetuses through the placenta, or milk and colostrum to puppies. A historical review was carried out on the reactivation of dormant larvae of T. canis in pregnant bitches which suggested that larval reactivation of T. canis is not solely the effect of a single hormone (prolactin) but is the result of a series of events triggered by progesterone, prolactin, and estrogens. In the first third of gestation, progesterone is capable of directly stimulating the reactivation of larvae through hormonal receptors, indirectly downregulating the granulomatous proinflammatory response around dormant T. canis larvae, and directing the response to a Th2 profile with increased levels of antibodies and blood eosinophils. After a time, when progesterone levels decrease, prolactin and estrogen maintain larval stimulation through hormonal receptors and downregulation of Th1 and the granulomatous proinflammatory response. Collectively, these hormones play major roles in the reactivation of T. canis larvae in pregnant bitches. The series of complex events that occur during larval reactivation is a clear example of transregulation, in which host hormones regulate the vital functions of the parasite to positively influence its establishment and/or proliferation. Understanding larval reactivation from an immunoendocrine perspective helps us to comprehensively understand the complex parasite-host relationship of T. canis.

In approximately half of the recurrent spontaneous abortion (RSA) cases, the underlying cause is unknown. However, most unexplained miscarriages are thought to be linked to immune dysfunction. This review summarizes the current evidence regarding the immunological evaluations of patients with RSA, with potential implications for clinical research. The immune system plays a crucial role in the successful outcome of pregnancy, as it tolerates the semi-allogeneic fetus while offering protection to both the mother and fetus from pathogens. The maternal-fetal interface is the place where the crosstalk between various immune cells such as macrophages, dendritic cells, natural killer (NK) cells, and T cells takes place. An adequate balance is required between these immune cells for pregnancy to progress. In RSA, a dysregulation between these immune players is witnessed. For example, in RSA, NK cells are not increased but also undergo a change in their activity, manifested as cytotoxic decidual NK. Similarly, regulatory T cells, which are crucial for fostering a tolerant immune environment, are decreased in RSA women. Similarly, imbalances between T-helper (Th1, Th2, Th17) cell subsets have been implicated in RSA. Furthermore, the imbalance between pro-inflammatory M1 and anti-inflammatory M2 macrophage phenotypes has been documented, with studies indicating a predominance of M1 macrophages in RSA patients. Targeting immune imbalances with therapies such as immunoglobulin administration, TNF inhibitors, and anticoagulants may improve pregnancy outcomes in women with RSA.

Interleukin-4 (IL-4), which is traditionally associated with inflammation, has emerged as a key player in tissue regeneration. Produced primarily by T-helper 2 (Th2) and other immune cells, IL-4 activates endogenous lymphocytes and promotes M2 macrophage polarization, both of which are crucial for tissue repair. Moreover, IL-4 stimulates the proliferation and differentiation of various cell types, contributing to efficient tissue regeneration, and shows promise for promoting tissue regeneration after injury. This review explores the multifaceted roles of IL-4 in tissue repair, summarizing its mechanisms and potential for clinical application. This review delves into the multifaceted functions of IL-4, including its immunomodulatory effects, its involvement in tissue regeneration, and its potential therapeutic applications. We discuss the mechanisms underlying IL-4-induced M2 macrophage polarization, a crucial process for tissue repair. Additionally, we explore innovative strategies for delivering IL-4, including gene therapy, protein-based therapies, and cell-based therapies. By leveraging the regenerative properties of IL-4, we can potentially develop novel therapies for various diseases, including chronic inflammatory disorders, autoimmune diseases, and organ injuries. While early research has shown promise for the application of IL-4 in regenerative medicine, further studies are needed to fully elucidate its therapeutic potential and optimize its use.

Haemonchus contortus (Barber pole worm) is one of the dominant helminth parasitic infections in small ruminants which is economically important and causes severe losses in the livestock industry, particularly in tropical and subtropical regions. This parasite resides in the abomasum and is responsible for severe blood loss, leading to anemia, emaciation, hypoproteinemia, weight loss, and potentially death. The economic impact of H. contortus on the livestock industry necessitates effective control measures, including early diagnosis and the development of effective vaccines. H. contortus secretes a variety of excretory and secretory proteins (ESPs), which are glycoproteins that play a crucial role in modulating the host's immune response. These ESPs are not only vital for understanding the immunological interactions between the parasite and the host but also serve as potential diagnostic tools and vaccine candidates. Similar ESPs have been identified in other parasitic species such as Cooperia spp, Ostertagia ostertagia, Teladorsagia circumcincta, Ascaris sum, Schistosoma japonicum, and Echinococcus multilocularis, underscoring their importance in both detection and vaccine development. In addition, there is a lack of highly potential specific proteins which having immunogenic properties that can be used for the accurate, early diagnosis serologically and serve as a potential candidate for the vaccine development against H. contortus. Recent research highlights that TH-9 stimulated proteins from H. contortus are emerging as promising candidates for vaccine development due to their immunomodulatory effects. These proteins have been shown to induce a TH-9 immune response, characterized by increased production of interleukin-9 (IL-9), which is critical for enhancing protective immunity against helminth infections. It is suggested to investigate TH-9 stimulated protein as potential candidates for vaccine development and diagnostic antigen.

Obstructive sleep apnoea (OSA) is a long-term disorder characterized by frequent blockages in the upper respiratory tract during sleep, often leading to abrupt awakenings, with or without a decrease in oxygen levels. The systematic review and meta-analysis aimed to assess the effect of continuous positive airway pressure therapy (CPAP) on blood interleukin (IL) levels of IL-6, IL-10, IL-18, IL-1β, IL-4, and IL-17 in OSA adults.

The published databases from PubMed, Scopus, Web of Science, and Cochrane Library were searched from 2003 to 2024, without any restrictions. The Review Manager software 5.3 was employed to compute effect sizes, which were presented as the standardized mean difference (SMD) along with a 95% confidence interval (CI).

In total, 320 records were identified through database searching; ultimately, 42 articles were included in the qualitative synthesis and then the meta-analysis. The CPAP therapy significantly reduces IL-6 levels, as indicated SMD=0.64 [95% CI: 0.35, 0.93] and P<0.0001. CPAP therapy significantly reduced IL-18 and IL-1β levels in adults with OSA, but there is no significant difference in IL-10, IL-4, or IL-17 levels. Age, blood sample, body mass index, ethnicity, and treatment duration for IL-6 and apnoea-hypopnea index with IL-10 levels were effective factors in the pooled results. Experimentally, there was an interaction between IL-18 and IL-1β.

CPAP therapy has a positive impact on inflammatory markers in OSA adults; remarkably, it reduces IL-6 and IL-1β levels. Nevertheless, more evidence (such as the role of ethnicity) and understanding of interactions are needed.

Stress and negative mood in pregnancy have been linked to less favorable birth outcomes, but the mechanisms underlying this effect remain largely unknown. We examined associations between emotions in pregnancy, pro- and anti-inflammatory cytokines (IFN-γ, IL-6, IL-8, IL-10, IL-12, IL-17, MCP-1, MIP-1β, TNF-α) and birth outcomes (gestational age at birth and birth weight) in a low-risk sample.

At each trimester of pregnancy, participants (N = 74) completed the Positive and Negative Affect Schedule, Perceived Stress Scale, Edinburgh Postnatal Depression Scale, and State-Trait Anxiety Inventory. They provided blood samples in the third trimester. Multivariate regression with a reduction of dimensionality (orthogonal projection to latent structures) was used to assess associations between maternal emotions, cytokine levels, and birth outcomes.

We found significant positive associations between negative mood (depressive symptoms in the second and third trimesters and negative affect in the third trimester) and anti-inflammatory cytokine IL-10 levels, and negative associations between maternal distress in the second and third trimesters and pro-/anti-inflammatory cytokine ratios (IFN-γ/IL-10, TNF-α/IL-10 and IL-6/IL-10). Higher levels of pro-inflammatory cytokines IFN-γ, IL-12, IL-17, and TNF-α were associated with younger gestational age at birth and lower birth weight.

We did not control for relevant factors such as social support, health-related behaviors, or cortisol levels.

Negative mood in mid- and late pregnancy may shift cytokine balance toward the anti-inflammatory cytokine dominance. Our results provide further evidence for the negative association between pro-inflammatory cytokines in late pregnancy and gestational age at birth/birth weight, which we observed even in a low-risk population.

Objective There is evidence that cytokine genes' single nucleotide polymorphisms could be the reasons behind female infertility. This study aimed to identify the role for Interleukin33 rs1048274 (G > A) and rs16924243 (T > C), Interleukin22 rs1397852121 (C > T), rs1295978671 (C > T) and rs2227483 (A > T), Interleukin17A rs2275913 (G > A,C) and Interleukin17F rs763780 (T > C), Interleukin13 1512 (A > C) and IL13 2044 (G > A), and Interleukin4 rs2243250 (C > T) and rs2070874 (C > T) gene polymorphisms in female infertility to gain a richly more detailed understanding of its genetic predisposition. Five distinct groups, each comprising 200 infertile women and 200 age-matched fertile controls, were recruited to each Interleukins (33, 22, 17, 13 and 4) in this case-control study and were genotyped by using an amplification refractory mutation system. Statistical analysis is conducted by SPSS software V. 22 and using Chi-square (χ2) and logistic regression tests. Strength of association was estimated by multiple-comparison correction, population structure test and Haplotype analysis. The study was approved by the Academic Ethics Committee and each enrolled patient signed an informed consent.Results Our statistical results revealed risk alleles in all of the substitution lines for women infertility. Current findings provided evidence that in the presence of Interleukin33 Ap-value rs1048274 = 0.002 and Cp-value rs16924243 < 0.0001, Interleukin 22Tp-value rs1397852121 < 0.0001 and Tp-value rs2227483 = 0.000, Interleukin17A Ap-value rs2275913 = 0.003 and Interleukin17F Cp-value rs763780 = 0.000 and Interleukin13 Cp-value 1512 = 0.000 and Ap-value 2044 = 0.003, Interleukin4 Tp-value rs2243250 = 0.001 and Tp-value rs2070874 = 0.009 risk alleles, risk genotype also were significantly associated with increased chances of developing infertility. The relationship between risk genotypes and several well-established infertility risk factors including, polycystic ovary syndrome, premature ovarian failure, oophorectomy, diminished ovarian reserve, endometriosis, uterine fibroids, ovarian cysts, uterine polyps, fallopian tube blockage and thyroid dysfunction, also exhibited. This study suggests the significant role of interleukin gene polymorphisms in human reproductive success.

Gonorrhea, caused by the human-restricted pathogen Neisseria gonorrhoeae, is a commonly reported sexually transmitted infection. Since most infections in women are asymptomatic, the true number of infections is likely much higher than reported. How gonococci (GC) colonize women's cervixes without triggering symptoms remains elusive. Using a human cervical tissue explant model, we found that GC inoculation increased the local secretion of both proinflammatory (IL-1β and TNF-α) and antiinflammatory (IL-10) cytokines during the first 24 hours of infection. Cytokine induction required GC expression of Opa isoforms that bind the host receptors carcinoembryonic antigen-related cell adhesion molecules (CEACAMs). GC inoculation induced NF-κB activation in both cervical epithelial and subepithelial cells. However, inhibition of NF-κB activation, which reduced GC-induced IL-1β and TNF-α, did not affect GC colonization. Neutralizing IL-10 or blocking IL-10 receptors by antibodies reduced GC colonization by increasing epithelial shedding and epithelial cell-cell junction disassembly. Inhibition of the CEACAM downstream signaling molecule SHP1/2, which reduced GC colonization and increased epithelial shedding, decreased GC-induced IL-10 secretion. These results show that GC induce local secretion of IL-10, a potent antiinflammatory cytokine, at the cervix by engaging the host CEACAMs to prevent GC-colonizing epithelial cells from shedding, providing a potential mechanism for GC asymptomatic colonization in women.

The initial stage of biological pregnancy is referred to as implantation, during which the interaction between the endometrium and the fetus is crucial for successful implantation. Around 10% of couples undergoing in vitro fertilization and embryo transfer encounter recurrent implantation failure (RIF), a clinical condition characterized by the absence of implantation after multiple embryo transfers. It is believed that implantation failure may be caused by inadequate or excessive endometrial inflammatory responses during the implantation window, as the female immune system plays a complex role in regulating endometrial receptivity and embryo implantation. Recent approaches to enhance the likelihood of pregnancy in RIF patients have focused on modifying the mother's immune response during implantation by regulating inflammation. Long non-coding RNAs (lncRNAs) play a significant role in gene transcription during the inflammatory response. Current research suggests that dysfunctional lncRNAs are linked to various human disorders, such as cancer, diabetes, allergies, asthma, and inflammatory bowel disease. These non-coding RNAs are crucial for immune functions as they control protein interactions or the ability of RNA and DNA to form complexes, which are involved in differentiation, cell migration, and the production of inflammatory mediators. Given the apparent involvement of the immune system in RIF and the modulatory effect of lncRNAs on the immune system, this review aims to delve into the role of lncRNAs in immune system modulation and their potential contribution to RIF.

Pig production, a vital sector of the meat industry, faces demands for improved quality, efficiency, and sustainability. Advancements in breeding, disease control, and artificial insemination have enhanced production, while biotechnologies such as in vitro embryo production (IVP) and genetic engineering offer further progress. In vitro embryo production could facilitate the global exchange of valuable genetic material, accelerate breeding programs, and improve productivity, and it is essential for generating genetically modified (GM) pigs. These GM pigs have two main applications: first, they allow for targeted modifications aimed at improving production traits relevant to pig production in agriculture, such as meat quality and disease resistance. Second, they serve as valuable biomedical models for human disease research, regenerative medicine, and organ transplantation. Yet, despite notable advancements in recent decades, the efficiency of the current IVP systems for porcine embryos remains a challenge. Compared to the in vivo environment, suboptimal culture conditions lead to issues such as elevated polyspermy, poor embryo development, and the production of low-quality blastocysts. This review provides an overview of the key steps and recent advancements in porcine IVP technology. We will emphasize the promising utilization of oocytes from live females of high genetic value through ovum pick-up and the incorporation of extracellular vesicles and cytokines into IVP media. These innovative strategies hold immense potential to significantly enhance embryo development and overall success rates in porcine IVP, and could open the door for significant progress in both agriculture and biomedicine applications.

Preeclampsia (PE) is a life-threatening disease of pregnancy and a prominent cause of neonatal and maternal mortality and morbidity. PE affects approximately 5-10% of pregnancies worldwide, posing significant risks to perinatal and maternal health. It is characterized by a variety of interconnected pathological cascades contributing to the stimulation of intravascular inflammation, oxidative stress (OS), endothelial cell activation, and syncytiotrophoblast stress that converge on a common pathway, ultimately resulting in disease progression. The present study was designed and executed to review the existing scientific literature, specifically focusing on the etiology (gestational diabetes mellitus and maternal obesity, insulin resistance, metabolic syndrome, maternal infection, periodontal disease, altered microbiome, and genetics), clinical presentations (hypertension, blood disorders, proteinuria, hepatic dysfunction, renal dysfunction, pulmonary edema, cardiac dysfunction, fetal growth restrictions, and eclampsia), therapeutic clinical biomarkers (creatinine, albuminuria, and cystatin C) along with their associations and mechanisms in PE. In addition, this study provides insights into the potential of nanomedicines for targeting these mechanisms for PE management and treatment. Inflammation, OS, proteinuria, and an altered microbiome are prominent biomarkers associated with progression and PE-related pathogenesis. Understanding the molecular mechanisms, exploring suitable markers, targeted interventions, comprehensive screening, and holistic strategies are critical to decreasing the incidence of PE and promoting maternal-fetal well-being. The present study comprehensively reviewed the etiology, clinical presentations, therapeutic biomarkers, and preventive potential of nanomedicines in the treatment and management of PE.

Physical activity (PA) during pregnancy has numerous benefits, which may be mediated via effects on the immune system. However, supportive evidence is inconsistent and is mainly from studies in high-risk groups. We estimated the effect of PA during pregnancy on systemic inflammatory markers and cytokines in mothers recruited in the Barwon infant study.

The Barwon infant study is a prebirth cohort of 1064 mothers recruited in the Barwon Region of Victoria, Australia. Participants reported their previous week's PA at their 28-week antenatal appointment using the International PA Questionnaire. Women were grouped into low, moderate, and high PA categories based on daily duration and weekly frequency of walking, moderate- or vigorous-intensity PA. Women reporting moderate levels of PA, consistent with current recommendations, served as the comparison group. Markers of systemic inflammation, high-sensitivity C-reactive protein (hsCRP), glycoprotein acetyls (GlycA), and 17 cytokines were measured at 28 weeks gestation and log transformed as appropriate. Regression analyses adjusted for maternal smoking, gestational diabetes mellitus, prepregnancy BMI, and household size were performed.

Compared to women in the moderate group (n = 371, 42%), women reporting low PA (n = 436, 50%) had 10.1% higher hsCRP (95% CI (3.7% to 16.6%), p < 0.01) while women in high PA (n = 76, 9%) had a 14% higher hsCRP (95% CI (3.1% to 24.8%), p = 0.01). Women in the high PA category had higher interleukin (IL)-4 (q = 0.03) and IL-9 (q = 0.03) levels compared to those in moderate category. Each vigorous MET minute/week was associated with lower GlycA (β = -0.004, 95% CI (-0.044 to 0.035); p = 0.03).

Low and high PA are each associated with higher hsCRP than moderate PA, suggesting that undertaking the recommended moderate PA during pregnancy decreases systemic inflammation. High PA affects T cell-associated cytokines during pregnancy. Evidence from our study suggests that PA can modulate the immune responses during pregnancy. Studies are now required to assess whether PA during pregnancy impacts maternal and infant clinical outcomes by modifying inflammatory responses.

Cytokines coordinate the intricate choreography of the immune system, directing cellular activities that mediate inflammation, pathogen defense, pathology and tissue repair. Within this spectrum, the anti-inflammatory prowess of interleukin-10 (IL-10) predominates in immune homeostasis. In normal pregnancy, the dynamic shift of IL-10 across trimesters maintains maternal immune tolerance ensuring fetal development and pregnancy success. Unravelling the dysregulation of IL-10 in pregnancy complications is vital, particularly in the heightened inflammatory condition of preeclampsia. Of note, a reduction in IL-10 levels contributes to endothelial dysfunction. In human immunodeficiency virus (HIV) infection, a complex interplay of IL-10 occurs, displaying a paradoxical paradigm of being immune-protective yet aiding viral persistence. Genetic variations in the IL-10 gene further modulate susceptibility to HIV infection and preeclampsia, albeit with nuanced effects across populations. This review outlines the conceptual framework underlying the role of IL-10 in the duality of normal pregnancy and preeclampsia together with HIV infection, thus highlighting its regulatory mechanisms and genetic influences. Synthesizing these findings in immune modulation presents avenues for therapeutic interventions in pregnancy complications comorbid with HIV infection.

The secondary injuries following traumatic spinal cord injury (SCI) is a multiphasic and complex process that is difficult to treat. Although methylprednisolone (MP) is the only available pharmacological regime for SCI treatment, its efficacy remains controversial due to its very narrow therapeutic time window and safety concerns associated with high dosage. In this study, we have developed an oil-in-gel type of organohydrogel (OHG) in which the binary oleic-water phases coexist, for the local delivery of MP. This new OHG is fabricated by a glycol chitosan/oxidized hyaluronic acid hydrophilic network that is uniformly embedded with a biocompatible oil phase, and it can be effectively loaded with MP or other hydrophobic compounds. In addition to spatiotemporally control MP release, this biodegradable OHG also provides a brain tissue-mimicking scaffold that can promote tissue regeneration. OHG remarkably decreases the therapeutic dose of MP in animals and extends its treatment course over 21 d, thereby timely manipulating microglia/macrophages and their associated with signaling molecules to restore immune homeostasis, leading to a long-term functional improvement in a complete transection SCI rat model. Thus, this OHG represents a new type of gel for clinical treatment of secondary injuries in SCI.

Oxidative stress (OS) and endoplasmic reticulum stress (ERS) are at the genesis of placental disorders observed in preeclampsia, intrauterine growth restriction, and maternal hypothyroidism. In this regard, cationic manganese porphyrins (MnPs) comprise potent redox-active therapeutics of high antioxidant and anti-inflammatory potential, which have not been evaluated in metabolic gestational diseases yet. This study evaluated the therapeutic potential of two MnPs, [MnTE-2-PyP]5+ (MnP I) and [MnT(5-Br-3-E-Py)P]5+ (MnP II), in the fetal-placental dysfunction of hypothyroid rats. Hypothyroidism was induced by administration of 6-Propyl-2-thiouracil (PTU) and treatment with MnPs I and II 0.1 mg/kg/day started on the 8th day of gestation (DG). The fetal and placental development, and protein and/or mRNA expression of antioxidant mediators (SOD1, CAT, GPx1), hypoxia (HIF1α), oxidative damage (8-OHdG, MDA), ERS (GRP78 and CHOP), immunological (TNFα, IL-6, IL-10, IL-1β, IL-18, NLRP3, Caspase1, Gasdermin D) and angiogenic (VEGF) were evaluated in the placenta and decidua on the 18th DG using immunohistochemistry and qPCR. ROS and peroxynitrite (PRX) were quantified by fluorometric assay, while enzyme activities of SOD, GST, and catalase were evaluated by colorimetric assay. MnPs I and II increased fetal body mass in hypothyroid rats, and MnP I increased fetal organ mass. MnPs restored the junctional zone morphology in hypothyroid rats and increased placental vascularization. MnPs blocked the increase of OS and ERS mediators caused by hypothyroidism, showing similar levels of expression of HIFα, 8-OHdG, MDA, Gpx1, GRP78, and Chop to the control. Moreover, MnPs I and/or II increased the protein expression of SOD1, Cat, and GPx1 and restored the expression of IL10, Nlrp3, and Caspase1 in the decidua and/or placenta. However, MnPs did not restore the low placental enzyme activity of SOD, CAT, and GST caused by hypothyroidism, while increased the decidual and placental protein expression of TNFα. The results show that treatment with MnPs improves the fetal-placental development and the placental inflammatory state of hypothyroid rats and protects against oxidative stress and reticular stress caused by hypothyroidism at the maternal-fetal interface.

Osteoarthritis (OA) is one of the leading causes of joint dysfunction and disability in the elderly, posing serious social problems and a huge socio-economic burden. Existing pharmacological treatments have significant drawbacks, and searching for an effective pharmacological intervention is an urgent priority. Recent studies have demonstrated the chondroprotective, anabolic, and anti-catabolic properties of avocado-soybean unsaponifiable (ASU), a natural plant extract made from avocado and soybean oils, consisting of the remainder of the saponified portion of the product that cannot be made into soap. The main components of ASU are phytosterols, beta-sitosterol, canola stanols, and soya stanols, which are rapidly incorporated into cells. Studies have confirmed the anti-inflammatory, antioxidant, and analgesic properties of phytosterols. ASU slows down the progression of OA primarily by inhibiting pathways involved in the development of OA disease. ASU prevents cartilage degradation by inhibiting the release and activity of matrix metalloproteinases and by increasing the tissue inhibition of these catabolic enzymes; ASU is also involved in the inhibition of the activation of nuclear factor κB (NF-κB) which is a transcriptional inhibitor that regulates the inflammatory response of chondrocytes. NF-κB is a transcription factor that regulates the inflammatory response of chondrocytes, and inhibition of the transfer of the transcription factor NF-κB from the cytoplasm to the nucleus regulates the transcription of many pro-inflammatory factors. By appealing to the mechanism of action and thus achieving anti-inflammatory, anti-catabolic, and pro-synthetic effects on cartilage tissues, AUS is clinically responsive to the reduction of acute pain and OA symptom progression. This paper aims to summarize the studies on the use of avocado-soybean unsaponifiable in the pharmacological treatment of osteoarticular.

Maternal immunologic mechanisms for tolerance are essential for a successful pregnancy because they prevent maladaptive immune responses to the placenta and semi-allogeneic fetus and promote fetal growth. Preeclampsia is a major global cause of fetal mortality and morbidity. It is characterized by new-onset hypertension and proteinuria that occurs at twenty weeks of pregnancy or later. Preeclampsia is defined by a rise in cytokines that are pro-inflammatory and antiangiogenic components in the fetoplacental unit and the vascular endothelium of pregnant women, as well as an excessive and increasing stimulation of the immune system. Crucially, inflammation can result in low birth weight and inadequate placental perfusion in neonates. Preeclampsia, which is ultimately connected to inflammatory responses, can be impacted by several immunological mechanisms. Our goal in this work was to compile the most recent research on the pathoimmunology of preeclampsia, including studies on angiogenic variables and, in particular, immunological components.

Gastroesophageal reflux disease is frequently observed and has no definitive treatment. There are 2 main views on the pathogenesis of gastroesophageal reflux disease. The first is that epithelial damage starts from the mucosa by acidic-peptic damage and the inflammatory response of granulocytes. The other view is that T-lymphocytes attract chemoattractants from the basal layer to the mucosa, and granulocytes do not migrate until damage occurs. We aim to investigate the inflammatory processes occurring in the esophageal epithelium of the phenotypes at the molecular level. We also examined the effects of these changes on tissue integrity.

Patients with mild and severe erosive reflux, nonerosive reflux, reflux hypersensitivity, and functional heartburn were included. Inflammatory gene expressions (JAK/STAT Signaling and NFKappaB Primer Libraries), chemokine protein levels, and tissue integrity were examined in the esophageal biopsies.

There was chronic inflammation in the severe erosion group, the acute response was also triggered. In the mild erosion group, these 2 processes worked together, but homeostatic cytokines were also secreted. In nonerosive groups, T-lymphocytes were more dominant. In addition, the inflammatory response was highly triggered in the reflux hypersensitivity and functional heartburn groups, and it was associated with physiological reflux exposure and sensitivity.

"Microinflammation" in physiological acid exposure groups indicates that even a mild trigger is sufficient for the initiation and progression of inflammatory activity. Additionally, the anti-inflammatory cytokines were highly increased. The results may have a potential role in the treatment of heartburn symptoms and healing of the mucosa.

In order to identify and possibly offer prophylactic treatment to women at risk for preterm birth (PTB), novel prediction models for PTB are needed. Our objective was to utilize high-sensitive plasma protein profiling to investigate whether early prediction of spontaneous PTB (sPTB) before 34 gestational weeks (gw) was possible in a low-risk population.

A case-control study was conducted on 46 women with sPTB before 34 gw and 46 women with normal pregnancies and term deliveries. Prospectively collected plasma sampled at gw 11 (range 7-16) and gw 25 (range 23-30) was analyzed with a high-sensitivity Proximity Extension Assay for levels of 177 inflammation-associated proteins, and statistically processed with multivariate logistic regression analysis.

In the first trimester, higher levels of hepatocyte growth factor (HGF) were associated with sPTB <34 gw (OR 1.49 (1.03-2.15)). In the second trimester, higher levels of interleukin (IL)-10 (OR 2.15 (1.18-3.92)), IL-6 (OR 2.59 (1.34-4.99)), and the receptor activator of nuclear factor κB (RANK) (OR 2.18 (1.26-3.77)) were associated with sPTB <34 gw. The area under the curve for the prediction models including these proteins was 0.653 (0.534-0.759) in the first trimester and 0.854 (0.754-0.925) in the second trimester.

A combination of inflammation-associated plasma proteins from the second trimester of pregnancy showed a good predictive ability regarding sPTB before 34 gw, suggesting it could be a valuable supplement for the assessment of the clinical risk of sPTB. However, although a high number (n=177) of plasma proteins were analyzed with a high-sensitivity method, the prediction of sPTB in the first trimester remains elusive.

Musculoskeletal (MSK) pathology encompasses an array of conditions that can cause anything from mild discomfort to permanent injury. Their prevalence and impact on disability have sparked interest in more effective treatments, particularly within orthopedics. As a result, the human placenta has come into focus within regenerative medicine as a perinatal derivative (PnD). These biologics are sourced from components of the placenta, each possessing a unique composition of collagens, proteins, and factors believed to aid in healing and regeneration. This review aims to explore the current literature on PnD biologics and their potential benefits for treating various MSK pathologies. We delve into different types of PnDs and their healing effects on muscles, tendons, bones, cartilage, ligaments, and nerves. Our discussions highlight the crucial role of immune modulation in the healing process for each condition. PnDs have been observed to influence the balance between anti- and pro-inflammatory factors and, in some cases, act as biologic scaffolds for tissue growth. Additionally, we assess the range of PnDs available, while also addressing gaps in our understanding, particularly regarding biologic processing methods. Although certain PnD biologics have varying levels of support in orthopedic literature, further clinical investigations are necessary to fully evaluate their impact on human patients.

Malaria remains a significant global health challenge, demanding a deeper understanding of host immune responses for effective clearance of the parasitic infection. Cytokines, as crucial mediators of the immune system, orchestrate a complex interplay during the various stages of malaria infection. Throughout the course of the disease, an intricate balance of pro-inflammatory and anti-inflammatory cytokines dictate the immune response's outcome, influencing parasitic clearance and disease severity. During the initial stages, interleukins such as interleukin-12 (IL-12), interferon-gamma (IFN-γ), and tumour necrosis factor-alpha (TNF-α) play pivotal roles in activating innate immune cells, initiating the anti-parasitic response. Simultaneously, regulatory cytokines like interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β) modulate this immune activation, preventing excessive inflammation and tissue damage. As the infection progresses, a delicate shift occurs, characterized by a transition to adaptive immunity, guided by cytokines like interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-13 (IL-13), promoting antibody production and T-cell responses. Notably, the resolution of malaria infection crucially relies on a fine-tuned balance of cytokine networks. Dysregulation or imbalances in these mediators often result in immune hyperactivation, contributing to severe manifestations and prolonged infection. Understanding the multi-faceted roles of cytokines in malaria clearance offers promising avenues for therapeutic interventions. Targeting cytokine pathways to restore immune equilibrium or bolster protective responses could potentially enhance treatment strategies and vaccine development. In conclusion, the pivotal role of cytokines in immunomodulation during malaria clearance underscores their significance as potential targets for therapeutic interventions, offering promising prospects in the global fight against this infectious disease.

Prenatal exposure to inflammation is related to the risk for cognitive impairment in offspring. However, mechanisms underlying the link between inflammatory cytokines at the maternal-fetal interface and human cognitive development are largely unknown. This study addressed this research gap by examining whether i) cytokines within the placenta are associated with different domains of neurocognitive development during infancy, and ii) if DHEA-S in cord blood mediates these associations. We also explored the role of early-life socioeconomic status (SES) in moderating the effect of fetal adrenal steroids on cognitive development in low- and middle-income country contexts. A cohort of 242 mother-infant dyads in Leyte, the Philippines participated in the study and all of them were followed from early pregnancy until 12-months. Concentrations of pro- and anti-inflammatory cytokines in the placenta, and DHEA-S in cord blood collected at delivery were evaluated. The multifactorial aspects of the infant's cognitive functioning were assessed based on the Bayley Scales of Infant Development, third edition (BSID-III). We used Structural Equation Modelling (SEM) with an orthogonal rotation to examine associated paths among latent variables of pro- and anti-inflammatory cytokines in the placenta, fetal neuroendocrine factors, and cognitive development. Pathway analyses showed that both pro- and anti-inflammatory cytokines in the placenta were indirectly related to cognitive (p < 0.05) and language developmental outcomes (p < 0.1) via DHEA-S in cord blood among the low SES group. Yet, we found no statistically significant indirect effect of pro- or anti-inflammatory cytokines on neurocognitive development among the high SES sub-sample. This study extends our understanding of how early-life socioeconomic conditions modify biological pathways underlying the relationship between prenatal factors and postpartum cognitive development.

A weakened immune system and more inflammatory cytokines being released are possible effects of the surgical stress that a cesarean section induces. This kind of reaction, in addition to the altered reaction to catecholamines, has the potential to significantly affect the immune system of the mother and the patients' general postoperative course. This prospective study compared the plasma levels of catecholamines and cytokines in healthy pregnant patients having cesarean sections under spinal anesthesia versus general anesthesia. A total of 30 pregnant women undergoing elective cesarean sections were divided into two groups: 15 who received general anesthesia (GA) and 15 who received spinal anesthesia (SA). Blood samples were collected from all subjects before anesthesia induction (pre-OP), 6 h postoperatively (6 h post-OP), and 12 h (12 h post-OP), to measure levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), IL-8, IL-4, IL-10, norepinephrine (NE), and epinephrine (EPI). When we compared the two groups, we discovered that only IL-6 and IL-4 had significantly higher levels pre-OP, whereas all studied cytokines exhibited an increase in the GA versus SA group at 6 and 12 h post-OP. In the case of catecholamines, we discovered that serum levels are positively related with pro-inflammatory or anti-inflammatory cytokines, depending on the time of day and type of anesthetic drugs. Compared to SA, GA has a more consistent effect on the inflammatory response and catecholamine levels. The findings of this study confirm that the type of anesthesia can alter postoperative immunomodulation to various degrees via changes in cytokine and catecholamine production. SA could be a preferable choice for cesarean section because it is an anesthetic method that reduces perioperative stress and allows for less opioid administration, impacting cytokine production with proper immunomodulation.

One of the critical cases of recurrent pregnancy loss is immunological factors, whereas obtaining effective prevention or treatment is necessary for cognition of reasons.

In this study, we tried to evaluate some immunological factors related to recurrent pregnancy loss.

This case-control study was conducted on 66 women at the age of 18-35 yr who were referred to the Clinic of Gynecology and Obstetrics, Ali Ibn Abi Taleb hospital, Zahedan, Iran, from August-December 2019. Interleukin 33 (IL-33) serum levels were measured using enzyme-linked immunosorbent assay. Immunoglobulin G, Immunoglobulin A, Immunoglobulin M (IgM), and C-reactive protein levels were measured by serology and hematology methods.

The mean age of total participants was 30.8 ± 3.80 yr. The mean serum IL-33 in the case group was 318.5 ± 254.1 pg/ml and was lower than the control group (354.2 ± 259.9 pg/ml), which was not statistically significant (p = 0.52). The level of C-reactive protein in the case and control was not significantly different (p = 0.27), and Immunoglobulin A and Immunoglobulin G in the case and control were also not significantly different (p = 0.46, and p = 0.16, respectively), but there were significant differences (p = 0.003) between the level of the IgM in the case and control groups.

No statistically significant difference was observed in the IL-33 serum level, for at least 4-6 months after the last abortion in the case group and the final live birth in the control group. In contrast, serum levels of IgM were statistically significant. Finally, the need for more studies is felt according to the different results of the previous studies in this field.

Chronic inflammation brought on by oxidative stress can result in several immunopathologies. Natural compounds with antioxidant characteristics, like quercetin, have shown effectiveness in reducing oxidative damage and regulating the immune response.

The commonly used food additive monosodium glutamate (M) causes immunosuppression by disrupting redox equilibrium and inducing oxidative stress. The goal of this work is to examine the therapeutic potential of quercetin against immunotoxicity brought on by M, revealing the molecular route implicated in such immunopathology by targeting the thymus and spleen, to support the development of future anti-inflammatory and antioxidant therapies.

M-fed rats were employed as an immunotoxicity model and were supplemented with quercetin for four weeks. Hematological and biochemical parameters were measured; H&E staining, immunohistochemistry, flow cytometry, real-time quantitative PCR, and western blotting were performed.

Based on the findings, TLR4 was activated by M to cause oxidative stress-mediated inflammation, which was alleviated by the supplementation of quercetin by modulating redox homeostasis to neutralize free radicals and suppress the inflammatory response. To prevent M-induced inflammation, quercetin demonstrated anti-inflammatory functions by blocking NF-kB activation, lowering the production of pro-inflammatory cytokines, and increasing the release of anti-inflammatory cytokines. By normalizing lipid profiles and lowering the potential risk of immunological deficiency caused by M, quercetin also improves lipid metabolism. Additionally, it has shown potential for modifying insulin levels, suggesting a possible function in controlling M-induced alteration in glucose metabolism. The addition of quercetin to M enhanced the immune response by improving immunoglobulin levels and CD4/CD8 expression in the thymus and spleen. Additionally, quercetin inhibited apoptosis by controlling mitochondrial caspase-mediated cellular signaling, suggesting that it may be able to halt cell death in M-fed rats.

The results of this study first indicate that quercetin, via modulating redox-guided cellular signaling, has a promising role in reducing immune disturbances. This study illuminates the potential of quercetin as a safe, natural remedy for immunopathology caused by M, including thymic hypoplasia and/or splenomegaly, and paves the way for future anti-inflammatory and antioxidant supplements.

Changes in cervical length in twin pregnancies exhibit various patterns, but it is unclear whether the mechanism underlying spontaneous preterm birth (sPTB) is consistent. The existence of detailed phenomena in singleton pregnancies is also unclear.

To explore the different patterns in cervical length trajectories in singleton and twin pregnancies and to analyze whether the immunological mechanisms of sPTB are consistent among these cervical length patterns.

This cohort study recruited pregnant individuals who received antenatal care and delivered at Peking University Third Hospital in Beijing, China, between January 1, 2014, and December 31, 2022. Individuals with singleton and twin pregnancies were included.

Cervical length measurements and white blood cell (WBC) indicators.

The primary outcome was sPTB. Longitudinal trajectory cluster analysis was used to identify patterns of changes in cervical length in singleton and twin pregnancies. A random-effects model with cubic spline was used to fit and compare the longitudinal trajectory of WBC indicators among early preterm birth, moderate to late preterm birth, and term birth.

A total of 43 559 pregnant individuals were included; of these, 41 706 had singleton pregnancies (mean [SD)] maternal age, 33.0 [4.0] years) and 1853 had twin pregnancies (mean [SD] maternal age, 33.3 [3.6] years). Two distinct patterns of cervical length changes were observed in both singleton and twin pregnancies: shortened (21 366 singletons and 546 twins) and stable (20 340 singletons and 1307 twins). In singleton pregnancies, WBC count was associated with early sPTB in individuals with both shortened cervix (odds ratio [OR], 1.35; 95% CI, 1.00-1.82) and stable cervix (OR, 1.64; 95% CI, 1.07-2.50). However, for twin pregnancies, the association of WBC count (OR, 3.13; 95% CI, 1.58-6.18) with the risk of early sPTB was observed only in individuals with a shortened cervix.

This study identified 2 distinct cervical length patterns: shortened and stable. These patterns revealed 2 preterm birth mechanisms in twin pregnancies, with the immunopathogenesis of sPTB found only in the shortened cervix pattern; in singleton pregnancies, maternal immune response was associated with a higher risk of sPTB regardless of a shortened or stable cervix.

Currently, the primary treatment for gastroesophageal reflux is acid suppression with proton pump inhibitors, but they are not a cure, and some patients don't respond well or refuse long-term use. Therefore, alternative therapies are needed to understand the disease and develop better treatments. Laparoscopic anti-reflux surgery (LARS) can resolve symptoms of these patients and plays a significant role in evaluating esophageal healing after preventing harmful effects. Successful LARS improves typical gastroesophageal reflux symptoms in most patients, mainly by reducing the exposure time to gastric contents in the esophagus. Amelioration of the inflammatory response and a recovery response in the esophageal epithelium is expected following the cessation of the noxious attack.

To explore the role of inflammatory biomolecules in LARS and assess the time required for esophageal epithelial recovery.

Of 22 patients with LARS (pre- and post/5.8 ± 3.8 months after LARS) and 25 healthy controls (HCs) were included. All subjects underwent 24-h multichannel intraluminal impedance-pH monitoring and upper gastrointestinal endoscopy, during which esophageal biopsy samples were collected using endoscopic techniques. Inflammatory molecules in esophageal biopsies were investigated by reverse transcription-polymerase chain reaction and multiplex-enzyme-linked immunosorbent assay.

Post-LARS samples showed significant increases in proinflammatory cytokines [interleukin (IL)-1β, interferon-γ, C-X-C chemokine ligand 2 (CXCL2)], anti-inflammatory cytokines [CC chemokine ligand (CCL) 11, CCL13, CCL17, CCL26, CCL1, CCL7, CCL8, CCL24, IL-4, IL-10], and homeostatic cytokines (CCL27, CCL20, CCL19, CCL23, CCL25, CXCL12, migration inhibitory factor) compared to both HCs and pre-LARS samples. CCL17 and CCL21 levels were higher in pre-LARS than in HCs (P < 0.05). The mRNA expression levels of AKT1, fibroblast growth factor 2, HRAS, and mitogen-activated protein kinase 4 were significantly decreased post-LARS vs pre-LARS. CCL2 and epidermal growth factor gene levels were significantly increased in the pre-LARS compared to the HCs (P < 0.05).

The presence of proinflammatory proteins post-LARS suggests ongoing inflammation in the epithelium. Elevated homeostatic cytokine levels indicate cell balance is maintained for about 6 months after LARS. The anti-inflammatory response post-LARS shows suppression of inflammatory damage and ongoing postoperative recovery.

There is a substantial need of effective drugs for the treatment of hearing loss, which affects nearly 500 million individuals globally. Hearing loss can be the result of intense or prolonged noise exposure, ototoxic drugs, infections, and trauma, which trigger inflammatory signaling cascades that lead to irreversible damage to cochlear structures. To address this, we developed and characterized a series of covalent conjugates of anti-inflammatory drugs to hyaluronic acid (HA), for potential use as topical ototherapeutics. These conjugates were tested in in vitro assays designed to mirror physiological processes typically observed with acoustic trauma. Intense noise exposure leads to macrophage recruitment to the cochlea and subsequent inflammatory damage to sensory cells. We therefore first tested our conjugates' ability to reduce the release of inflammatory cytokines in macrophages. This anti-inflammatory effect on macrophages also translated to increased cochlear cell viability. In our initial screening, one conjugate, ibuprofen-HA, demonstrated significantly higher anti-inflammatory potential than its counterparts. Subsequent cytokine release profiling of ibuprofen-HA further confirmed its ability to reduce a wider range of inflammatory markers, to a greater extent than its equivalent unconjugated drug. The conjugate's potential as a topical therapeutic was then assessed in previously developed tympanic and round window membrane tissue permeation models. As expected, our data indicate that the conjugate has limited tympanic membrane model permeability; however, it readily permeated the round window membrane model and to a greater extent than the unconjugated drug. Interestingly, our data also revealed that ibuprofen-HA was well tolerated in cellular and tissue cytocompatibility assays, whereas the unconjugated drug displayed significant cytotoxicity at equivalent concentrations. Moreover, our data highlighted the importance of chemical conjugation of ibuprofen to HA; the conjugate had improved anti-inflammatory effects, significantly reduced cytotoxicity, and is more suitable for therapeutic formulation. Overall, this work suggests that ibuprofen-HA could be a promising safe and effective topical ototherapeutic for inflammation-mediated cochlear damage.

Preterm birth rates are consistently higher in African American (AA) pregnancies compared to White pregnancies in the United States. Neighborhood racial composition, experiences of racial discrimination, and systemic inflammation are factors that have been associated with preterm birth and other adverse pregnancy outcomes that may account for these disparities. Here, we investigated whether perceived neighborhood racial composition and experiences of discrimination were predictive of cytokine levels during pregnancy among AA individuals.

545 AA individuals completed surveys and had blood samples collected at prenatal clinics in the Midwest at three timepoints (8-18,19-29, and 30-36 weeks gestation) throughout pregnancy. Pro-inflammatory [interferon (IFN)-γ, interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α, macrophage migration inhibitory factor (MIF)] and anti-inflammatory cytokines (IL-10) were quantified. Multivariate and multilevel models were used to examine associations of perceived neighborhood racial composition and experiences of racial discrimination with cytokine levels, controlling for relevant covariates.

Perceived neighborhood racial composition was significantly associated with MIF at 30-36 weeks gestation in multivariate regression (p < 0.001). Living in neighborhoods with more compared to fewer White people was predictive of higher levels of MIF (b = 0.599, SE = 0.12, p < 0.001). Experiences of discrimination were also associated with higher levels of MIF (β = 0.141, SE = 0.07, p = 0.036). Neither predictor was associated with other cytokines. Follow-up analyses revealed that neighborhood racial composition was also predictive of higher MIF levels at 8-18 weeks gestation (p = 0.02) and at 19-29 weeks gestation (p = 0.04).

Living in neighborhoods with more White individuals and having more lifetime experiences of racial discrimination were positively related to levels of the pro-inflammatory cytokine, MIF, among pregnant AA individuals. MIF's known positive relationships with chronic stress and preterm birth suggest that these elevations in MIF may have negative health consequences. Future studies should explore whether MIF serves as a pathway between neighborhood racial composition or experiences of racial discrimination and preterm birth risk among AA individuals.

The microbiota residing in the gut environment is essential for host homeostasis. Increasing evidence suggests that microbial perturbation (dysbiosis) regulates cancer initiation and progression at local and distant sites. Here, we have identified microbial dysbiosis with the depletion of commensal bacteria as a host-intrinsic factor associated with metastatic dissemination to the bone. Using a mouse model of triple-negative mammary cancer, we demonstrate that a pre-established disruption of microbial homeostasis using an antibiotic cocktail increases tumor growth, enhanced circulating tumor cells, and subsequent dissemination to the bone. We found that the presence of pathogenic bacteria and loss of commensal bacteria in an antibiotic-induced gut environment is associated with sustained inflammation. Increased secretion of G-CSF and MMP-9 in intestinal tissues, followed by increased neutrophil infiltration and severe systemic inflammation in tumor-bearing mice, indicates the direct consequence of a dysbiotic microbiome. Increased neutrophil infiltration to the bone metastatic niche facilitates extravasation and transendothelial migration of tumor cells. It provides a novel, pre-established, and favorable environment to form an immunosuppressive pre-metastatic niche. The presence of tumor cells in immunosuppressive metastatic tumor niche disrupts the balance between osteoblasts and osteoclasts, promotes osteoclast differentiation, and remodels the bone structure. Excessive bone resorption by osteoclasts causes bone degradation and ultimately causes extreme pain in a bone metastatic mouse model. In clinical settings, bone metastasis is associated with intractable severe pain that severely compromises the quality of life in these patients.

The early-stage placental barrier is characterized by a lack of fetal circulation and by a thick trophoblastic barrier, whereas the later-stage placenta consists of vascularized chorionic villi encased in a thin, differentiated trophoblast layer, ideal for nutrient transport. In this work, predictive models of early- and late-stage placental transport are created using blastocyst-derived placental stem cells (PSCs) by modulating PSC differentiation and model vascularization. PSC differentiation results in a thinner, fused trophoblast layer, as well as an increase in human chorionic gonadotropin secretion, barrier permeability, and secretion of certain inflammatory cytokines, which are consistent with in vivo findings. Further, gene expression confirms this shift toward a differentiated trophoblast subtype. Vascularization results in a molecule type- and size-dependent change in dextran and insulin permeability. These results demonstrate that trophoblast differentiation and vascularization have critical effects on placental barrier permeability and that this model can be used as a predictive measure to assess fetal toxicity of xenobiotic substances at different stages of pregnancy.

Background: Breast milk (BM) is a nutritive fluid that is rich in bioactive components such as hormones and cytokines that can shape the newborn's feeding habits and program the newborn's immature immune system. BM components can change under different scenarios that include maternal body mass index (BMI) and premature birth. This study aimed to study the interaction of premature status or maternal obesity on the hormonal and cytokine profile in BM according to the sex of the offspring. Materials and Methods: We recruited 31 women with preterm births from the Centro de Alta Especialidad Dr. Rafael Lucio in Mexico. Luminex multiplexing assay was used for quantifying cytokine profile of monocyte chemoattractant protein-1, tumor necrosis factor (TNF)-α, interferon-γ, interleukin (IL)1-β, IL-2, IL-4, IL-6, IL-7, and hormones insulin, ghrelin, leptin, and glucagon in mature BM samples. Biological modeling was performed to predict the interaction between cytokines and hormones, maternal BMI status, infant birth sex, parity, and gestational age. Results: BM multiplex analysis showed positive correlations for TNF-α and increasing prematurity and for higher maternal BMI and IL-2, IL-4, and IL-6 cytokines. Multiple regression models identified an interaction between maternal BMI and gestational weeks in male infants that is associated to TNF-α accumulation in BM. Biological modeling predicts that preterm delivery in mothers with obesity modulates TNF- α levels in mature BM of women with male offspring. Conclusion: Prematurity and obesity modify BM's immune profile. TNF- α expression increases as prematurity increases, and maternal BMI correlates positively with increases in IL-2, IL-6, and IL-4. Our multiple regression model also shows that maternal BMI and gestational weeks in male infants predict TNF-α.