Prenatal maternal stress may lead to adverse pregnancy outcomes such as preterm birth and low birth weight. Our team has demonstrated in multiple rat models that prenatal maternal stress modifies the expression of inflammatory and stress regulators in the uterus and that this is transgenerationally passed over multiple generations through the female progeny. In this study, we investigated if male progeny exposed to ancestral prenatal maternal stress could also transmit changes to cause fetal programming of reproductive organs, leading to adverse pregnancy outcomes. We created a paternal transgenerational prenatal stress rat model. Dams (F0) were exposed to chronic variable stress during pregnancy, and their F1 male offspring stressed in utero were bred with control females for two generations. Gestational lengths and litter sizes were unchanged. Elevated gene expression of pro-inflammatory molecules in the uteri of F2 and F3 offspring was observed. Uterine expression of stress markers in the F2 and F3 females also increased even though plasma corticosterone levels were unchanged. Changes in the testicular expression of inflammatory and stress markers were also transmitted through the paternal lineage. These changes, however, tended to bear anti-inflammatory and adaptive functions, indicating compensatory mechanisms at play. These results demonstrate that fetal programming of uterine and testicular gene expression patterns can be transmitted through male progeny exposed to prenatal maternal stress.

Group B streptococcus is a common microbial agent associated with spontaneous preterm birth and fetal inflammatory response syndrome. In this study, we evaluated the utility of rytvela, a novel peptide antagonist of the interleukin-1 receptor, to suppress inflammatory activation, prolong gestation and improve neonatal outcomes induced in mice by Group B streptococcus. Pregnant mice were administered rytvela or PBS on gestation day 16.5, immediately prior and following surgical administration of heat-killed Group B streptococcus (hkGBS) or PBS into the uterine cavity. Treatment with rytvela prevented preterm delivery and alleviated fetal demise in utero and in the perinatal phase elicited by hkGBS. Compared to pups exposed to hkGBS alone, pups of dams co-administered rytvela exhibited substantially improved survival and growth through to weaning. Analysis by qPCR showed expression of inflammatory cytokine genes Il1b, Il6, Tnf, and Ifng in uterine tissues, and Il1b, Il6, and Tnf in fetal membranes, were stimulated by hkGBS and this increase was suppressed by co-administration of rytvela. Premature induction of uterine activation gene Ptgs2 in the myometrium was also attenuated by rytvela treatment. These data show that activation of IL1-mediated signaling in response to Group B streptococcus triggers an inflammatory cascade that causes preterm parturition and fetal inflammatory injury, and that rytvela can suppress inflammatory mediators to substantially improve pregnancy and fetal outcomes. Our findings add to accumulating evidence supporting clinical investigation of rytvela for fetal protection and delaying preterm birth.

OBJECTIVES:Intimate partner violence (IPV) poses serious risks to women's health, especially during pregnancy. Despite pregnancy being a key opportunity for IPV screening, various barriers often hinder health care provider efforts to screen for IPV. This study seeks to understand from IPV survivors how health care providers can better screen for and address IPV during pregnancy. METHODS:Women who had experienced IPV during pregnancy were recruited via Facebook ads. A website provided study details and a consent form. After consenting, participants completed a survey covering 4 main themes: personal demographics, IPV screening in pregnancy, barriers to disclosure, and interventions offered. Written comments were invited in addition to survey completion. RESULTS:This pilot study involved 23 participants who experienced IPV during pregnancy. Overall, 17 reported childhood abuse and 19 had experienced abuse outside of pregnancy. Although all participants supported IPV screening by health care providers during prenatal care, only 8 were screened. There was a preference for written tools over verbal assessments to enhance comfort and privacy. Barriers to disclosure included fear of partner retaliation, discomfort discussing IPV, concerns about confidentiality, and potential involvement of child protection services. Interventions offered were limited, with mental health support and social services identified as critical resources. CONCLUSIONS:Findings support the need for improved screening practices and comprehensive support systems to address the complex needs of pregnant individuals experiencing IPV, particularly given its prevalence and ties to childhood trauma. Enhancing standardized guidelines, health care provider training, and disclosure support are essential for promoting healthier outcomes for mothers and their children.

Agouti-related peptide (AgRP) is a well-established potent orexigenic peptide primarily expressed in hypothalamic neurons. Nevertheless, the expression and functional significance of extrahypothalamic AgRP remain poorly understood. In this study, utilizing histological and molecular biology techniques, we have identified a significant expression of Agrp mRNA and AgRP peptide production in glomus type I cells within the mouse carotid body (CB). Furthermore, we have uncovered evidence supporting the expression of the AgRP receptor melanocortin receptor 3 (Mc3r) in adjacent sympathetic neurons, suggesting a potential local paracrine role for AgRP within the CB. Importantly, AgRP immunoreactivity was also identified in glomus type I cells of the human CB. Given the unexpected abundance of AgRP in glomus type I cells, a chemoreceptor cell specialized in oxygen sensing, we proceeded to investigate whether Agrp expression in the CB is regulated by hypoxemia and associated oxygen- sensing molecular mechanisms. In vitro luciferase assays reveal that hypoxia stimulates the human and mouse Agrp promoters in a Hypoxia Inducible Factor (HIF1/2)-dependent manner. Our in vivo experiments further demonstrate that exposure to environmental hypoxia (10%) robustly induces Agrp expression in type I glomus cells of mice. Furthermore, these findings collectively highlight the hitherto unknown source of AgRP in murine and human type I glomus cells and underscore the direct control of Agrp transcription by HIF signaling. (c) 2025 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Social isolation and loneliness during pregnancy can negatively impact maternal and offspring health. Here we report that maternal social isolation in pregnant rats generates a distinct physiological and behavioural phenotype in 4th generation great-great-grandoffspring. Male and female F4 offspring born to lineages of transgenerational prenatal stress (TPS, i.e. the F0 mother was socially isolated before and during pregnancy), multigenerational prenatal stress (MPS, where gestational isolation occurred in four consecutive generations), and group-housed controls were tested at 6, 12 and 18 months of age. Assessments included endocrine (corticosterone) and immune markers (IL-18, MCP-1 and M-CSF), motor and cognitive function, and brain morphology via in vivo magnetic resonance imaging (MRI) across the lifespan. Ancestral social isolation in F4 generation rats exacerbated aging-associated stress responses and elevated the production of proinflammatory cytokines and chemokines across all groups. Exploratory behaviours, skilled reaching, skilled walking, spatial learning and memory revealed a stress-sensitive phenotype in TPS males and females along with greater hippocampal and prefrontal cortex atrophy. Thus, maternal social isolation mainly represents a stressful challenge with lifelong consequences for future generations. By contrast, MPS females revealed superior reaching skills that indicate behavioural flexibility with adaptive benefits. The MPS model therefore allows interpretations about the origins of resilience in the face of ongoing stress. Both TPS and MPS shifted cognitive strategies indicative of accelerated aging. Thus, social isolation may represent a significant stressor with potential long-term consequences for future generations. These findings provide a conceptual framework for better risk prediction and prevention of developmental disabilities and aging-related disorders.

OBJECTIVE:Several groups of neurons in the NTS suppress food intake, including Prlh-expressing neurons (NTSPrlh cells). Not only does the artificial activation of NTSPrlh cells decrease feeding, but also the expression of Prlh (which encodes the neuropeptide PrRP) and neurotransmission by NTSPrlh neurons contributes to the restraint of food intake and body weight, especially in animals fed a high fat diet (HFD). We set out to determine roles for putative PrRP receptors in the response to NTS PrRP and exogenous PrRP-related peptides. METHODS:We used animals lacking PrRP receptors GPR10 and/or GPR74 (encoded by Prlhr and Npffr2, respectively) to determine roles for each in the restraint of food intake and body weight by the increased expression of Prlh in NTSPrlh neurons (NTSPrlhOX mice) and in response to the anorectic PrRP analog, p52. RESULTS:Although Prlhr played a crucial role in the restraint of food intake and body weight in HFD-fed control animals, the combined absence of Prlhr and Npffr2 was required to abrogate the restraint of food intake in NTSPrlhOX mice. p52 suppressed feeding independently of both receptors, however. CONCLUSIONS:Hence, each receptor can participate in the NTSPrlh-mediated suppression of food intake and body weight gain, while PrRP analog treatment can mediate its effects via distinct systems. While Prlhr plays a crucial role in the physiologic restraint of weight gain, the action of either receptor is capable of ameliorating obesity in response to enhanced NTSPrlh signaling.

Preterm birth (PTB) is a major cause of neonatal mortality and morbidity. Evidence supports a determinant role for interleukin-6 (IL-6) in the pathophysiology of PTB. Our group developed a small peptide, HSJ633, that antagonizes the interleukin-6 receptor (IL-6R). Binding assays performed on HEK-Blue IL-6 cells reveal that HSJ633 appears to bind to IL-6R on a site remote from the IL-6 binding domain. Concordantly, HSJ633 selectively inhibits STAT3 phosphorylation while preserving the activation of cytoprotective AKT, p38, and ERK 1/2. In vivo, in a murine model of LPS-induced PTB, HSJ633 reduces inflammation in gestational and fetal tissues, preserves the integrity of fetal organs, and improves the survival of neonatal progeny when administered before and after the induction of labor by an inflammatory stimulus. Relevantly, the pharmacological inhibition of STAT3 in mice is sufficient to prevent PTB. Findings reveal first-in-class efficacy of a small peptide inhibitor of IL-6R, namely HSJ633, in impeding the inflammatory cascade associated with PTB and mitigating adverse neonatal outcomes.

Intrauterine inflammation is a significant cause of early preterm birth and fetal injury. There is a lack of effective interventions for intrauterine inflammation. This study aimed to determine whether direct fetal treatment with IL-1 receptor antagonists (IL-1RA), specifically anakinra (competitive IL-1RA) or rytvela (allosteric IL-1RA), could reduce intrauterine inflammation caused by intraamniotic injection of E. coli lipopolysaccharides (LPS) in a sheep model of pregnancy. We hypothesized the fetal intramuscular administration of IL1-RA therapy would comprehensively resolve intrauterine inflammation caused by LPS in the pregnant sheep model. Date-mated Merino ewes carrying single fetuses were randomized into four groups: LPS Group (10 mg intraamniotic LPS injection followed by saline), RYTVELA Group (10 mg LPS injection followed by 5 mg rytvela), ANAKINRA Group (LPS injection followed by 100 mg anakinra), and SALINE Group (saline injection followed by saline). All LPS-exposed fetuses had elevated bilirubin levels, leukopenia, and increased inflammatory mediators IL-1β, IL-8, tumour necrosis factor alpha (TNFα), and monocyte chemoattractant protein 1 (MCP-1) in amniotic fluid and lung tissue. Both anakinra and rytvela treatments reduced immunocyte infiltration in chorioamniotic membranes and lungs, and microglial staining, and increased the oligodendrocyte staining, but did not significantly resolve overall inflammation compared to the SALINE Group. In conclusion, fetal intramuscular administration of anakinra and rytvela did not effectively resolve intrauterine inflammation but showed potential in reducing tissue invasion and brain injury markers. These findings suggest that modest inflammation reduction may protect against brain injury and preterm birth, though no additional benefit was observed compared to intraamniotic IL-1RA treatment.

Anecdotal reports and preliminary clinical trials suggest that the psychoactive alkaloid ibogaine and its active metabolite noribogaine have powerful anti-addictive properties, producing long-lasting therapeutic effects across a range of substance use disorders and co-occurring neuropsychiatric diseases such as depression and post-traumatic stress disorder. Here we report a gram-scale, seven-step synthesis of ibogaine from pyridine. Key features of this strategy enabled the synthesis of three additional iboga alkaloids, as well as an enantioselective total synthesis of (+)-ibogaine and the construction of four analogues. Biological testing revealed that the unnatural enantiomer of ibogaine does not produce ibogaine-like effects on cortical neuron growth, while (−)-10-fluoroibogamine exhibits exceptional psychoplastogenic properties and is a potent modulator of the serotonin transporter. This work provides a platform for accessing iboga alkaloids and congeners for further biological study. Preliminary clinical trials suggest that ibogaine and its active metabolite noribogaine have powerful anti-addictive properties, Now, a strategy for the scalable, asymmetric total synthesis of ibogaine has been developed that also provides access to iboga analogues. Biological testing identified a psychoplastogenic iboga analogue that is a potent modulator of the serotonin transporter.

Intracellular calcium (Ca2+) is ubiquitous to cell signaling across biology. While existing fluorescent sensors and reporters can detect activated cells with elevated Ca2+ levels, these approaches require implants to deliver light to deep tissue, precluding their noninvasive use in freely behaving animals. Here we engineered an enzyme-catalyzed approach that rapidly and biochemically tags cells with elevated Ca2+ in vivo. Ca2+-activated split-TurboID (CaST) labels activated cells within 10 min with an exogenously delivered biotin molecule. The enzymatic signal increases with Ca2+ concentration and biotin labeling time, demonstrating that CaST is a time-gated integrator of total Ca2+ activity. Furthermore, the CaST readout can be performed immediately after activity labeling, in contrast to transcriptional reporters that require hours to produce signal. These capabilities allowed us to apply CaST to tag prefrontal cortex neurons activated by psilocybin, and to correlate the CaST signal with psilocybin-induced head-twitch responses in untethered mice. CaST is a Ca2+-activated version of split-TurboID. The tool allows labeling active neurons quickly, simply by administration of exogenous biotin, thus enabling the study of behaviors that would be impaired by hardware required for the use of other, light-dependent tools.

This review examines the complexities of preterm birth (PTB), emphasizes the pivotal role of inflammation in the pathogenesis of preterm labor, and assesses current available interventions. Antibiotics, progesterone analogs, mechanical approaches, nonsteroidal anti-inflammatory drugs, and nutritional supplementation demonstrate a limited efficacy. Tocolytic agents, targeting uterine activity and contractility, inadequately prevent PTB by neglecting to act on uteroplacental inflammation. Emerging therapies targeting toll-like receptors, chemokines, and interleukin receptors exhibit promise in mitigating inflammation and preventing PTB.