bims-simsho 2025-12-14 papers

bims-simsho

Biomed News

on Systems immunology and sex hormones

Issue of 2025–12–14
28 papers selected by
Chun-Chi Chang, Lunds universitet

Sex-Specific Metabolic Programming in Human Neutrophil Subsets.
Modeling the interplay of sex hormones in cardiac hypertrophic signaling.
Oxidative Stress-Telomere Axis in IVF: Molecular Mechanisms, Biomarkers, and Clinical Translation.
SENP5 acts as a downstream target of androgen receptor and contributes to prostate cancer growth.
Sex differences in testosterone and hematocrit levels reflect mating system differences of two Arctic-breeding shorebird species.
Neuroimmune modulatory effects of the NLRP3 inflammasome: the role of sex and living environment in brain affecting conditions.
Sex-specific angiogenic responses in endothelial cells-role of the pluripotency factor OCT4.
ZBTB7B modulates the androgen receptor as an upstream regulator via colocalization and direct binding in LNCaP prostate cancer cells.
BPTF regulates androgen receptor activity by enhancing chromatin accessibility and stabilizing the AR-FOXA1 interaction.
Longitudinal changes in sex hormones in a population of older community dwelling men.
The vaginal microbiota, symptoms, and local immune correlates in transmasculine individuals using sustained testosterone therapy.
A novel peptide explicitly induces prostate cancer cell death by destabilizing AR and inhibiting AR-mediated transcription.
The changing immune landscape of innate-like T cells and other innate cells throughout life.
Gut microbiota dysbiosis drives stroke-associated pneumonia: mechanisms and targeted therapeutic strategies.
From menses to ovulation: the immunomodulatory role of monocyte cytokines in menstrual cycle physiology and reproductive health - a narrative review.
Memories are I(F)N-credibly protective.
A focused evaluation of genetic and epigenetic contributions to common infertility conditions.
Anti-androgenic compound Embelin ameliorates polycystic ovary syndrome by reversing the ovarian dysfunction and associated metabolic irregularities in 5α-DHT-induced PCOS rats.
Anti-neuraminidase and anti-HA stalk antibodies reduce the susceptibility to and infectivity of influenza A/H3N2 virus.
Estrogen Receptor Alpha Contributes to Intestinal Inflammation in a Murine Model of Ileitis.
A review of immunometabolic crosstalk in PCOS-related pregnancy loss: mechanisms and emerging therapeutic strategies.
Immune-mediated mechanisms and maternal-fetal interface dysfunction in obstetric antiphospholipid syndrome.
Effect of oral contraceptive pretreatment on IVF outcomes in women with polycystic ovary syndrome using a long GnRH agonist protocol.
Identifying the mediating role of immune cells on the relationship between plasma lipidomes and PCOS: a two-step Mendelian randomization analysis.
SEX HORMONES INFLUENCE ORMDL3 EXPRESSION: IMPLICATIONS FOR SEX-ASSOCIATED ASTHMA PHENOTYPE.
17β-estradiol mediates sex-biased progesterone receptor expression via estrogen receptor α in chicken pituitary.
Unraveling sexually dimorphic offspring behaviors: maternal premating stress and the neuro-microbial-metabolic network.
Sex differences in the blood metabolome of extremely preterm infants: a pilot study on the impact of antibiotic therapy.

J Leukoc Biol. 2025 Dec 12. pii: qiaf179. [Epub ahead of print]

Sex-Specific Metabolic Programming in Human Neutrophil Subsets.

Anjali S Yennemadi, Faye K Murphy, Joseph Keane, Gina Leisching.

  While sex differences in neutrophil metabolism have been documented, whether this metabolic dimorphism extends to specific neutrophil subsets remains unknown.LDNs are characterized by their lower buoyant density compared to normal-density neutrophils(NDNs), are present in low numbers in healthy individuals, and are often associated with disease severity and immune dysregulation.LDNs and normal-density neutrophils (NDNs) from healthy human donors were isolated whereafter cellular metabolism specifically oxidative phosphorylation and glycolysis, alongside flow cytometry for maturity markers (CD16hi/lo) was assessed.Male LDNs exhibited significantly higher basal OCR and ATP production than female LDNs, while no sex differences were observed in NDNs. Strikingly, male LDNs also had higher OCR and glycolysis than their matched NDNs, whereas female LDNs were exhibited a lower OCR than their NDNs.Our study reveals subset-specific sexual metabolic reprogramming in LDNs whereby male LDNs exhibit a hypermetabolic phenotype. These findings provide a metabolic basis for sex-biased immune responses and highlight the need for sex-stratified approaches in neutrophil-targeted therapies.

Keywords:  Low density neutrophils; metabolism; mitochondria; neutrophils; oxygen consumption rate; sex difference

DOI:  https://doi.org/10.1093/jleuko/qiaf179
PLoS Comput Biol. 2025 Dec 10. 21(12): e1012895

Modeling the interplay of sex hormones in cardiac hypertrophic signaling.

Adhithi Lakshmikanthan, Minnie Kay, Pim J A Oomen.

Biological sex plays a crucial role in the outcomes of cardiac health and therapies. Sex hormones are known to strongly influence cardiac remodeling through intracellular signaling pathways, yet their underlying mechanisms remain unclear. To address this need, we developed and validated a logic-based systems biology model of cardiomyocyte hypertrophy that, for the first time, incorporates the effects of both estradiol (E2) and testosterone (T) alongside well-established hypertrophic stimuli (Strain, angiotensin II (AngII), and endothelin-1 (ET-1)). We qualitatively validated the model to literature data with 82% agreement. Quantitative validation was done by simulating the impact of the inputs (E2, T, Strain, AngII, and ET-1) on cardiac hypertrophy, captured as change in CellArea. We perturbed the validated model to examine the differential response to hypertrophy and identify changes in influential and sensitive downstream nodes for a pre-menopausal female, post-menopausal female, younger male, and older male condition. Our model shows how T and E2 interact with each other and other hypertrophic stimuli, with T demonstrating a more potent hypertrophic effect than E2. This model increases our understanding of the mechanisms through which sex hormones influence cardiac hypertrophy and can aid with developing more effective cardiac therapies for all patients.

DOI: https://doi.org/10.1371/journal.pcbi.1012895
Int J Mol Sci. 2025 Nov 24. pii: 11359. [Epub ahead of print]26(23):

Oxidative Stress-Telomere Axis in IVF: Molecular Mechanisms, Biomarkers, and Clinical Translation.

Charalampos Voros, Fotios Chatzinikolaou, Georgios Papadimas, Spyridon Polykalas, Ioakeim Sapantzoglou, Aristotelis-Marios Koulakmanidis, Diamantis Athanasiou, Vasiliki Kanaka, Maria Kanaka, Kyriakos Bananis, Antonia Athanasiou, Aikaterini Athanasiou, Ioannis Papapanagiotou, Charalampos Tsimpoukelis, Maria Anastasia Daskalaki, Marianna Theodora, Nikolaos Thomakos, Panagiotis Antsaklis, Dimitrios Loutradis, Georgios Daskalakis.

  The reduction in oocyte competence and ovarian reserve coincides with reproductive ageing; nevertheless, the molecular mechanisms underlying this phenomenon remain poorly understood. Our testable mechanistic hypothesis is that the oxidative stress-telomere axis is a crucial regulatory mechanism controlling meiotic stability, mitochondrial resilience, and granulosa cell integrity. This notion posits that granulosa and cumulus cells have accelerated telomere attrition and impaired DNA-damage responses due to elevated amounts of reactive oxygen species, which also induce oxidative guanine lesions, inhibit telomerase function, and generate telomeric replication stress. This telomere-dependent vulnerability is anticipated to compromise developmental competence, disrupt meiotic spindle integrity, and diminish metabolic support to the oocyte, prior to observable declines in AMH or follicle count. Data from human IVF cohorts supports the model: Conditions such as PCOS, endometriosis, and POI have unique oxidative-telomeric profiles, whereas diminished telomere length in granulosa cells, reduced telomerase activity, and worse fertilisation, blastulation, and pregnancy outcomes are associated with increased follicular oxidative DNA damage. The findings suggest that oxidative DNA damage (8-OHdG), telomerase activity, and the structure of granulosa-cell telomeres may serve as preliminary indicators of preclinical ovarian ageing. This theory may be directly evaluated in forthcoming longitudinal studies and specific treatments related to telomerase regulation, mitochondrial medicines, or redox modulation. Consequently, the oxidative stress-telomere axis may represent a vital physiologic factor affecting reproductive lifespan and a prospective target for personalised ART techniques.

Keywords:  DNA damage (8-OHdG); SIRT1-FOXO-NRF2-AMPK axis; assisted reproductive technology; biological ovarian aging; cumulus–oocyte complex; endometriosis; follicular fluid; granulosa cells; in vitro fertilization; mitochondrial dysfunction; oocyte quality; ovarian reserve; oxidative stress; polycystic ovary syndrome; reproductive aging; shelterin complex; telomerase activity; telomeres

DOI:  https://doi.org/10.3390/ijms262311359
Oncol Lett. 2026 Feb;31(2): 51

SENP5 acts as a downstream target of androgen receptor and contributes to prostate cancer growth.

Ximin Chen, Xubo Gong, Jingcheng Zhang, Weiwei Liu.

  The androgen receptor (AR) signaling pathway plays an important role in prostate cancer (PCa) progression. In the present study, a significant co-expression was found between SENPs and AR. In addition, SENP5 was obviously negatively correlated with overall survival and disease-free survival in patients with PCa. Moreover, SENP5 silencing markedly inhibited the proliferation of PCa cells. Chromatin immunoprecipitation quantitative PCR assays further confirmed that AR could transcriptionally activate SENP5 expression. In summary, the present results suggested that SENP5 acts as a downstream target of AR and contributes to PCa growth, the underlying molecular mechanism of which needs further investigation.

Keywords:  SENP5; androgen receptor; prognosis; prostate cancer

DOI:  https://doi.org/10.3892/ol.2025.15404
Behav Ecol. 2025 Nov-Dec;36(6):36(6): araf136

Sex differences in testosterone and hematocrit levels reflect mating system differences of two Arctic-breeding shorebird species.

Johannes Krietsch, Wolfgang Goymann, Mihai Valcu, Bart Kempenaers.

  Sex steroids, such as testosterone, are critical for the development of secondary sexual characteristics and shape traits beneficial for competition over mates and resources. Testosterone profiles may thus differ depending on variation in female and male mating strategies. Sex and mating system differences may also be found in hematocrit profiles, given elevated hematocrit levels during energetically demanding life stages such as migration or during sexual competition. Thus, males of polygynous species should maintain higher testosterone and hematocrit throughout the breeding season compared to monogamous or polyandrous males. Less is known about how mating systems affect testosterone and hematocrit in females: a recent study found higher testosterone in females of classically polyandrous species with reversed sex roles compared to females with typical sex roles. Here we compare baseline and peak plasma testosterone levels (induced by injecting gonadotropin releasing hormone GnRH) and hematocrit values in polygynous pectoral sandpipers and in classically polyandrous red phalaropes. In males, baseline testosterone concentrations were higher in the polygynous than in the classically polyandrous species, whereas in females, this pattern was reversed, with testosterone concentrations tending to be higher in the classically polyandrous species than in the polygynous one. In both sexes, the magnitude of the GnRH-induced increase in testosterone did not differ between species. Hematocrit was higher in the sex with higher competition for mates: in pectoral sandpipers, males had higher hematocrit than females; in red phalaropes, females had higher hematocrit than males. In conclusion, our results show that physiological parameters partially reflect differences in mating strategies.

Keywords:  hematocrit; mating system; performance; polyandry; polygyny; sex roles; testosterone

DOI:  https://doi.org/10.1093/beheco/araf136
Front Immunol. 2025 ;16 1711656

Neuroimmune modulatory effects of the NLRP3 inflammasome: the role of sex and living environment in brain affecting conditions.

Miriam Ciani, Giovanna Rigillo, Beatrice Bertarini, Cristina Benatti, Silvia Alboni, Fabio Tascedda.

  The NLRP3 inflammasome is a master regulator of neuroinflammation, linking systemic perturbations to brain dysfunction and thereby influencing overall brain health. Its sensitivity to biological sex and environmental factors suggests that NLRP3 may act both as a contributor to sex-dependent disease mechanisms and a modifiable therapeutic target for pharmacological and non-pharmacological interventions. In this mini-review, we summarize emerging evidence on sex-specific differences in NLRP3 signaling that may contribute to disparities between males and females in disease incidence, symptomatology, and treatment response. Neuroinflammation-driven disorders, including atherosclerosis, neuropathic pain, substance use, and stress-related syndromes, show how sex influences NLRP3 inflammasome expression and activity with downstream effects on cognition and behavior. We also examine the modulatory influence of environmental factors, with emphasis on social behavior and environmental enrichment, as determinants of NLRP3 dynamics relevant to neurocognitive function and brain health. Overall, the findings suggest that NLRP3 acts as a central hub integrating sex and environmental influences, with broad implications for personalized interventions in brain-related disorders.

Keywords:  NLRP3 inflammasome; biological sex; central nervous system; enriched environment; exposome; pharmacology; social isolation

DOI:  https://doi.org/10.3389/fimmu.2025.1711656
Angiogenesis. 2025 Dec 12. 29(1): 10

Sex-specific angiogenic responses in endothelial cells-role of the pluripotency factor OCT4.

Junchul Shin, Junyoung Hong, Iuliia Molokotina, Irene Krukovets, Ellin Kim, Svyatoslav Tkachenko, Eugene Podrez, Tatiana V Byzova, Olga A Cherepanova.

  The study investigates the sex-specific effects of the pluripotency factor OCT4 deficiency in endothelial cells (ECs) on angiogenesis. OCT4 is known for its role in embryonic stem cells, but we recently found that it plays a protective role in ECs during atherosclerosis. Herein, we utilized cultured mouse aortic ECs (MAECs) and several in vivo models, including skin wounding, melanoma tumor implantation, and hindlimb ischemia, to explore the role of OCT4 in angiogenesis in both male and female mice. Our findings revealed significant sexual dimorphism in wild type mice, along with sex differences in responses to OCT4 deficiency across all three in vivo models. Male mice with endothelial Oct4 knockout had faster skin wound healing, increased vascularization, and quicker blood flow recovery after hindlimb ischemia than wild-type mice. In contrast, female mice with endothelial Oct4 knockout experienced delayed wound healing, no significant change in blood flow recovery after hindlimb ischemia, and increased tumor growth. Mechanistically, MCP1, a key angiogenic chemokine, was differentially regulated in male and female Oct4 knockout compared to wild-type MAECs, suggesting OCT4-dependent regulation of MCP1 as a critical mechanism for sex differences in angiogenic responses. RNA sequencing (RNAseq) analysis revealed distinct gene expression profiles in male and female MAECs upon OCT4 deficiency. Notably, female ECs exhibited upregulation of pro-inflammatory genes, which, although modest relative to their already elevated baseline, may contribute to the enhanced tumor growth observed in mutant females. In contrast, male ECs exhibited increased expression of cell cycle- and angiogenesis-related genes, correlating with their enhanced angiogenic responses. Overall, the research provides novel insights into the sex-specific functional role of OCT4 in ECs during angiogenesis and emphasizes the need for developing sex-specific EC-targeting therapeutic strategies for cardiovascular diseases and cancer.

Keywords:  Angiogenesis; Endothelial cells; OCT4; Sex differences

DOI:  https://doi.org/10.1007/s10456-025-10025-5
Transl Cancer Res. 2025 Nov 30. 14(11): 7598-7610

ZBTB7B modulates the androgen receptor as an upstream regulator via colocalization and direct binding in LNCaP prostate cancer cells.

Eunji Im, Su-Yeon Park, Deok-Yong Sim, Ah Reum Cho, Bum Ju Kil, Bonglee Kim, Bum-Sang Shim, Sung-Hoon Kim.

   Background: Though ZBTB7B is overexpressed in breast and prostate cancers and dysregulates CD8 T cell response, there is no report on the close relationship between ZBTB7B and androgen receptor (AR) yet. This study aimed to investigate the molecular interaction between ZBTB7B and AR and to determine its role in prostate cancer progression.
Methods: Prostate cancer cell lines (AR-dependent LNCaP and AR-independent DU145) were subjected to 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, clonogenic assay, and cell cycle analysis. Protein-protein interaction was examined using immunoprecipitation and immunofluorescence. Protein stability was assessed by cycloheximide chase and ubiquitination assays. RNA interference was employed to deplete ZBTB7B or AR, and tissue expression patterns were analyzed by The Cancer Genome Atlas (TCGA) and human tissue microarray.
Results: ZBTB7B was overexpressed in prostate cancer cells and tissues with poor prognosis by human tissue microarray and TCGA analysis. However, ZBTB7B depletion suppressed viability, the number of colonies and increased G1 arrest in AR dependent LNCaP cells, but not in AR independent DU145 cells. Interestingly, ZBTB7B depletion suppressed the expression of AR and prostate specific antigen (PSA) in LNCaP cells, while AR depletion did not affect ZBTB7B. Furthermore, AR inhibitor finasteride and AR activator dihydrotestosterone (DHT) did not affect ZBTB7B. However, ZBTB7B was colocalized with AR by immunofluorescence and was bound to AR by immunoprecipitation. Consistently, ZBTB7B depletion attenuated the nuclear translocation and stability of AR through its degradation and also promoted AR degradation by ubiquitination assay. Notably, N-terminal domain (NTD) of AR is requisite for binding with ZBTB7B in HEK293 cells, not AR-DNA-binding domain (DBD) or AR-ligand-binding domain (LBD) in HEK293 cells.
Conclusions: Overall, these findings provide a novel insight that ZBTB7B promotes prostate cancer progression as a potent oncogene via colocalization and binding with AR.

Keywords:  N-terminal domain of the androgen receptor (AR-NTD); ZBTB7B; androgen receptor (AR); dihydrotestosterone (DHT); finasteride; prostate cancer

DOI:  https://doi.org/10.21037/tcr-2025-1365
Nat Commun. 2025 Dec 11.

BPTF regulates androgen receptor activity by enhancing chromatin accessibility and stabilizing the AR-FOXA1 interaction.

Hee-Young Jeon, Sudeep Khadka, Majid Pornour, Hyunju Ryu, Hegang Chen, Arif Hussain, Hung-Ming Lam, Eva Corey, Htoo Zarni Oo, Martin Gleave, Xiaofang Che, Christopher Barbieri, Jianfei Qi.

BPTF, the scaffolding subunit of the nucleosome remodeling factor (NURF) complex, has been implicated in the progression of several malignancies, but its role in prostate cancer (PCa) remains unclear. Here, we demonstrate that BPTF is upregulated in castration-resistant prostate cancer (CRPC) and promotes disease progression. RNA-seq revealed that BPTF primarily enhances the expression of androgen receptor (AR) target genes. ChIP-seq showed that BPTF increases AR binding at promoters, enhancers and super-enhancers. ATAC-seq further demonstrated that BPTF increases chromatin accessibility to facilitate AR binding, in part through SMARCA1, a catalytic subunit of the NURF complex. Notably, BPTF/AR co-bound regions are highly enriched for FOXA1 motifs but only weakly enriched for AR motifs. We further show that BPTF forms a protein complex with AR and FOXA1, in which FOXA1 recruits the BPTF-AR complex to chromatin, while BPTF stabilizes the AR-FOXA1 interaction. Importantly, BPTF interacts with AR through its bromodomain, and a BPTF bromodomain inhibitor disrupts this interaction, impairs AR signaling and suppresses PCa cell growth. In summary, our findings establish BPTF as a critical regulator of AR activity by promoting chromatin accessibility and stabilizing the AR-FOXA1 complex, highlighting BPTF as a potential therapeutic target in prostate cancer.

DOI: https://doi.org/10.1038/s41467-025-67329-9
J Clin Endocrinol Metab. 2025 Dec 11. pii: dgaf652. [Epub ahead of print]

Longitudinal changes in sex hormones in a population of older community dwelling men.

Spencer T Hills, Tyler A Mansfield, Shalender Bhasin, Eric S Orwoll.

   CONTEXT: Based on cross-sectional studies and short longitudinal studies, levels of sex hormones (SH) change with age in men. However, there are limited data about SH in men over 80, and few longitudinal studies >10 years.
OBJECTIVE: The aim of this study was to characterize SH concentrations in older men, and assess long-term changes.
METHODS: We studied 477 community dwelling men, ages 78-97 years, who participated in the Osteoporotic Fractures in Men (MrOS) study. Medical history was obtained via clinical visits and questionnaires. Serum sex steroid levels (testosterone, estradiol, estrogen, dihydrotestosterone (DHT)) were assayed using liquid chromatography/mass spectrometry, free testosterone by equilibrium dialysis, and sex hormone binding globulin (SHBG) by radioimmunoassay. In 215 men, SH levels were compared to levels obtained 14.0±0.65 years earlier.
RESULTS: In cross sectional analyses, mean total testosterone levels were 413.9±180.0, with considerable variation among participants. In 21.4%, total T levels were <275 ng/dL. Similarly, directly measured free T levels were low (<6.6 ng/dL) in 37.6%. Total testosterone levels were modestly correlated with directly measured free T, estradiol, estrone, DHT and SHBG, and weakly negatively associated with BMI and smoking. In longitudinal analyses (n=215), average total testosterone, estradiol and estrone level decreased, while SHBG increased, but changes were highly variable. Among those with total T >275ng/dL at baseline, T levels decreased to <275 ng/dL in 20.5%.
CONCLUSIONS: In old men there was a broad range of total testosterone levels, and a significant fraction were in a range considered hypogonadal. In longitudinal analyses, although there was considerable interindividual variation, gradual declines in mean total testosterone continued in the 8th through 10th decades of life.

Keywords:  Age; Estradiol; Longitudinal; Male; SHBG; Testosterone

DOI:  https://doi.org/10.1210/clinem/dgaf652
Cell Rep. 2025 Dec 05. pii: S2211-1247(25)01404-4. [Epub ahead of print] 116632

The vaginal microbiota, symptoms, and local immune correlates in transmasculine individuals using sustained testosterone therapy.

Bern Monari, Hannah Wilcox, Priscilla Haywood, Pawel Gajer, Jorge Rojas-Vargas, David Zuanazzi, Lindsay Rutt, Ainslie Shouldice, Reeya Parmar, L Elaine Waetjen, Yonah Krakowsky, Emery Potter, Jessica L Prodger, Jacques Ravel.

  Transmasculine individuals (assigned female at birth, masculine gender identity, TM) may use gender-affirming testosterone therapy, and some report adverse genital symptoms during treatment. In cis women, the vaginal microbiota is central to reproductive and sexual health. Lactobacillus-dominant communities are considered optimal, while diverse, Lactobacillus-depleted microbiota are non-optimal. Prior studies suggest Lactobacillus deficiency in TM vaginal microbiota, but associations with symptoms and immune markers remain unclear. We launched the TransBiota study to characterize the TM vaginal microbiota, soluble mediators of local inflammation, and self-reported symptoms over three weeks. Fewer than 10% of TM possess Lactobacillus-dominant microbiota, and most exhibit diverse, Lactobacillus-depleted microbiota. We identify 11 vaginal microbiota community state types (tmCSTs), with Lactobacillus-dominant tmCSTs unexpectedly linked to abnormal odor and elevated interleukin-1α. However, Lactobacillus dominance is not associated with other key symptoms, such as dyspareunia and vaginal dryness, underscoring that microbiome-symptom relationships in TM are more complex and warrant further research.

Keywords:  16S rRNA gene; CP: microbiology; amplicon sequencing; gender-affirming care; local inflammation; microbiome; prevotella; testosterone therapy; transgender; transmasculine; vaginal microbiota

DOI:  https://doi.org/10.1016/j.celrep.2025.116632
Biochem Pharmacol. 2025 Dec 08. pii: S0006-2952(25)00881-0. [Epub ahead of print] 117616

A novel peptide explicitly induces prostate cancer cell death by destabilizing AR and inhibiting AR-mediated transcription.

Akanksha Agarwal, Aishani Patnaik, Ekta Gupta, Bharti Jaiswal, Ashish Gupta.

  Current treatment strategies for prostate cancer primarily focuses on regulating androgen receptor (AR) activity, either through androgen deprivation or the use of anti-androgen therapies. While these approaches are initially effective, many patients eventually develop resistance, resulting in the emergence of castration-resistant prostate cancer (CRPC). This transition not only complicates disease management but also leads to persistent side effects, underscoring the urgent need for alternative therapeutic strategies that directly target AR or disrupt its interactions with co-regulatory proteins. Given the deregulated expression and altered subcellular localization of TIP60, a key AR coregulator in prostate cancer, we hypothesized that interfering with the AR-TIP60 interaction could mitigate aberrant AR signaling. To investigate this, we selectively expressed the C-terminal region of TIP60 containing the nuclear receptor box (NRB) motif as a short peptide in prostate cancer cells and demonstrated that this peptide effectively disrupts the AR-TIP60 interaction and exerts broad suppressive effects on AR signaling. Importantly, the peptide selectively induces cell death in AR-positive prostate cancer cells. Mechanistic studies revealed that the peptide impairs AR signaling by inhibiting dihydrotestosterone (DHT)-mediated AR chromatin binding and promoting AR degradation via the proteasome pathway. Furthermore, in silico analyses suggest that the peptide directly binds to AR's N-terminal domain, leading to its structural destabilization. Collectively, these results identify a novel AR-targeting peptide with multifaceted inhibitory effects, offering a promising therapeutic avenue for AR-positive prostate cancers, particularly in treatment-resistant cases. The peptide holds potential for development as a standalone therapy or in combination with existing chemotherapeutic agents.

Keywords:  Androgen receptor; Nuclear receptor box motif; Prostate cancer; TIP60

DOI:  https://doi.org/10.1016/j.bcp.2025.117616
Immunol Cell Biol. 2025 Dec 10.

The changing immune landscape of innate-like T cells and other innate cells throughout life.

Marziyeh Taheri, Christopher Menne, Jeremy Anderson, Louis Perriman, Shuo Li, Stuart P Berzins, Paul V Licciardi, Thomas M Ashhurst, Sedigheh Jalali, Daniel G Pellicci.

  Spectral flow cytometry is an advanced immunological tool that can enable comprehensive analysis of the immune system by simultaneously comparing innate and adaptive immune cells. Here, using a 40-color antibody panel, we advance our knowledge of innate-like cells by investigating chemokine receptors and maturation markers not usually assessed on these populations, examining age-related effects on these immune cell subsets. We characterize phenotypic changes of peripheral blood mononuclear cells (PBMCs) in three age groups: newborns (cord blood), adults aged 20-30 years, and adults aged > 70 years. We compare the age-related changes of innate cells, including ILCs, NK cells, monocytes, dendritic cells, and innate-like T cells, comparing them with memory T cells. We also examine subsets of CD4-CD8- double-negative (DN) T cells and CD3+CD161+ T cells, revealing they are phenotypically similar to known subsets of innate-like T cells, and they also increase in frequency in an age-related manner. The frequencies of ILC1 increased with age, ILC2 remained stable, whereas ILC3 peaked in young adults, and were higher than cord and older adults. Notably, we identify the NK cell maturation marker, CD57, as a universal marker that defines aging populations of both innate and adaptive immune cells. This study enhances our understanding of the ontogeny of human immune cells, highlighting significant age-related changes in the frequency and phenotype of innate-like populations of immune cells.

Keywords:  CD markers; aging; immunophenotyping; innate cells; innate‐like T cells; spectral flow cytometry

DOI:  https://doi.org/10.1111/imcb.70070
Front Neurosci. 2025 ;19 1677744

Gut microbiota dysbiosis drives stroke-associated pneumonia: mechanisms and targeted therapeutic strategies.

Jun Xiao, Jing Xia, Zhiying Chen, Weiwei Zha, Tian Xu, Xulong Chen, Xiaoping Yin.

  The gut microbiota has been increasingly recognized as a central regulator of immune function, with growing research highlighting its association with the development of stroke-associated pneumonia (SAP). This review provides an overview of current research on the correlation between SAP and alterations in gut microbial composition and metabolism, with a focus on microbial imbalance, changes in key metabolites, and relevant biological mechanisms. Clinical and preclinical studies consistently report a decline in short-chain fatty acids (SCFAs)-producing bacteria, an increase in potentially harmful microbial species, reduced SCFAs levels, and elevated lipopolysaccharide (LPS) concentrations. These disturbances appear to be associated with SAP progression through the microbiota-gut-brain and microbiota-gut-lung axes by affecting immune regulation and inflammatory responses. The review also examines microbiota-targeted treatment approaches, including dietary modification, antibiotic therapy, probiotics, microbiota-regulating compounds, fecal microbiota transplantation (FMT), and respiratory microbiota transfer. A deeper understanding of how microbial disturbances are correlated with SAP may help explain the increased vulnerability to pulmonary infections following stroke and support the design of more effective, microbiota-based therapeutic strategies.

Keywords:  gut microbiota dysbiosis; microbiota gut brain axis; microbiota- gut lung axis; microecological therapy; stroke-associated pneumonia

DOI:  https://doi.org/10.3389/fnins.2025.1677744
Ann Med Surg (Lond). 2025 Dec;87(12): 8453-8459

From menses to ovulation: the immunomodulatory role of monocyte cytokines in menstrual cycle physiology and reproductive health - a narrative review.

Emmanuel Ifeanyi Obeagu, Getrude Uzoma Obeagu.

  Monocytes, as essential components of the immune system, play a pivotal role in regulating immune responses throughout the menstrual cycle. Their cytokine secretion is integral to immune modulation, influencing processes like endometrial remodeling, ovulation, and implantation. Cytokines such as interleukins, tumor necrosis factor (TNF), and growth factors secreted by monocytes help maintain a delicate balance between inflammation and immune tolerance, crucial for reproductive health. This balance facilitates both tissue repair and immune protection, ensuring proper function of the reproductive organs during the menstrual cycle. Dysregulation in monocyte cytokine secretion can contribute to a range of reproductive disorders, including endometriosis, polycystic ovary syndrome, and recurrent pregnancy loss. An overproduction of pro-inflammatory cytokines, such as TNF-α and interleukin-6, may lead to chronic inflammation, tissue damage, and impaired fertility. Conversely, inadequate secretion of anti-inflammatory cytokines can hinder the immune tolerance necessary for embryo implantation, potentially leading to complications like miscarriage. This review explores the pivotal role of monocytes and their cytokine secretion in maintaining reproductive health and their contribution to reproductive disorders.

Keywords:  cytokines; immune regulation; menstrual cycle; monocytes; reproductive health

DOI:  https://doi.org/10.1097/MS9.0000000000004021
Immunity. 2025 Dec 09. pii: S1074-7613(25)00518-7. [Epub ahead of print]58(12): 2923-2925

Memories are I(F)N-credibly protective.

Brydie R Huckestein, Paul G Thomas.

Lung-resident memory CD8+ T cells coordinate rapid antiviral defense mechanisms across lung compartments to quicky limit viral replication and spread. In this issue of Immunity, Mattingly et al. demonstrate the importance of CD8+ Trm cell-derived interferon-γ in epithelial reprogramming for barrier defense in humans.

DOI: https://doi.org/10.1016/j.immuni.2025.11.016
Ther Adv Reprod Health. 2025 Jan-Dec;19:19 26334941251399074

A focused evaluation of genetic and epigenetic contributions to common infertility conditions.

Sezgin Gunes, Elzem Nisa Alkan, Neslihan Hekim.

  Infertility is a complex condition influenced by genetic and biological factors. In men, it is often caused by abnormalities in chromosome number or structure, alterations in DNA structure, specific gene mutations, or missing segments of the Y chromosome. Recent studies have also highlighted the impact of epigenetic mechanisms-such as DNA methylation, histone modifications, and noncoding RNAs-on gene function and fertility. Abnormal methylation patterns, particularly in genes such as DNMT3A/B/L, H19, MEST, SOX30, and those involved in the piRNA pathway, have been linked to poor sperm production and reduced fertility. These epigenetic changes can lower sperm quality, impair embryo health, and decrease the chances of success with fertility treatments. The role of biological and epigenetic factors in female reproduction is more limited. This narrative review aims to examine well-established genetic and epigenetic mechanisms associated with infertility, with a focus on key molecular pathways and regulatory processes. A literature review was conducted to summarize the most relevant and recent publications addressing genetic and epigenetic mechanisms as contributing factors to human infertility.

Keywords:  epigenetics; female infertility; male infertility; sperm DNA methylation; sperm non-coding RNAs

DOI:  https://doi.org/10.1177/26334941251399074
Fitoterapia. 2025 Dec 08. pii: S0367-326X(25)00652-5. [Epub ahead of print] 107025

Anti-androgenic compound Embelin ameliorates polycystic ovary syndrome by reversing the ovarian dysfunction and associated metabolic irregularities in 5α-DHT-induced PCOS rats.

Sandeep Palakkil Mavilavalappil, Shabeer Ali Hassan Muhammed, Sandhya Mohan, M Divya Lakshmanan, Toine F Bovee, K Sreejith.

  We could successfully reverse the polycystic ovary syndrome (PCOS) in a rat model using an anti-androgenic compound extracted from Embelia tsjeriam-cottam, which exhibited spectral characteristics consistent with Embelin. The identity of the anti-androgenic fraction was confirmed as Embelin using FT-IR, UV spectrophotometry, and UPLC-MS/MS analyses. The anti-androgenic activity of the extracted Embelin was evaluated using the Yeast RIKILT Androgen Assay and compared against (i) 5α-dihydrotestosterone (5α-DHT), (ii) a commercially sourced Embelin standard, and (iii) flutamide, a known androgen receptor antagonist. In silico molecular docking studies further revealed that Embelin exerts its anti-androgenic effects by competitively binding to the ligand-binding domain of the androgen receptor (AR), with interaction energy values comparable to those of 5α-DHT and hydroxyflutamide. The embelin fraction (up to 100 μl) and in combination with 5α-DHT, was non-toxic and promoted normal cell proliferation in vitro. Further, the extract also efficiently scavenged the 5α-DHT-induced Reactive Oxygen Species generation and downregulated the 5α-DHT-induced androgen receptor (AR) expression significantly in the in vitro system. A PCOS rat model was successfully established through 5α-DHT induction. Embelin treatment effectively reversed several hallmark features of PCOS, including ovarian dysfunction (e.g., hypo-progesteronemia, follicular cysts, and estrous cycle irregularities) as well as metabolic disturbances such as insulin resistance, weight gain, dyslipidaemia, and adipocyte hypertrophy. In conclusion, this is the first study to demonstrate the therapeutic potential of Embelin in ameliorating PCOS-related ovarian and metabolic dysfunctions.

Keywords:  Androgen receptor; Embelin; Estrous cycle; Polycystic ovary syndrome

DOI:  https://doi.org/10.1016/j.fitote.2025.107025
Nat Commun. 2025 Dec 11. 16(1): 10910

Anti-neuraminidase and anti-HA stalk antibodies reduce the susceptibility to and infectivity of influenza A/H3N2 virus.

Gregory Hoy, Thomas Cortier, Hannah E Maier, Guillermina Kuan, Roger Lopez, Nery Sanchez, Sergio Ojeda, Miguel Plazaola, Daniel Stadlbauer, Abigail Shotwell, Angel Balmaseda, Florian Krammer, Simon Cauchemez, Aubree Gordon.

Immune responses against neuraminidase (NA) and hemagglutinin (HA) are critical for developing effective influenza vaccines, yet their role in influenza transmission remains unclear. We conducted household transmission studies in Managua, Nicaragua, to assess the impact of anti-NA and anti-HA antibodies induced by natural infection on influenza A/H3N2 susceptibility and infectivity. Using mathematical models capturing household transmission dynamics, we found that high pre-existing antibody levels against the HA head (>31, [95% CrI 13-67]), HA stalk (>35, [95% CrI 11-66]), and NA (>31, [95% CrI 12-68]) are associated with reduced susceptibility to infection (relative susceptibility: HA head, 0.63 [95% CrI 0.42-0.98]; HA stalk, 0.66 [95% CrI 0.44-0.99]; NA, 0.49 [95% CrI 0.30-0.76]). HA stalk (>58 [95% CrI: 47-70]) and NA (>27 [95% CrI: 15-43]) are associated with reduced infectivity (relative infectivity: NA, 0.55 [95% CrI: 0.32-0.98], HA stalk 0.53 [95% CrI: 0.27-0.97]). These findings suggest that influenza vaccines designed to elicit NA immunity in addition to HA immunity may not only enhance protection against infection but also reduce onward transmission.

DOI: https://doi.org/10.1038/s41467-025-65283-0
J Cell Immunol. 2025 ;7(4): 127-132

Estrogen Receptor Alpha Contributes to Intestinal Inflammation in a Murine Model of Ileitis.

Alyssia V Broncano, Wendy A Goodman.



Keywords:  Crohn’s disease; Estrogen; Estrogen receptor alpha; Estrogen receptor beta; Inflammation; Inflammatory bowel disease; SAMP ileitis

DOI:  https://doi.org/10.33696/immunology.7.232
Gynecol Endocrinol. 2025 Dec 31. 41(1): 2600160

A review of immunometabolic crosstalk in PCOS-related pregnancy loss: mechanisms and emerging therapeutic strategies.

Feng Zhang, Jian Wu, Liping Ge, Ying Huang, Yawen Huang.

   BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine-metabolic disorder affecting up to 18% of reproductive-aged women globally. Women with PCOS exhibit a significantly increased risk of miscarriage, independent of obesity and assisted reproduction variables. The etiology of PCOS-related pregnancy loss is multifactorial. Nevertheless, current clinical interventions target isolated mechanisms and demonstrate limited efficacy in reducing miscarriage rates.
OBJECTIVE: This review synthesize recent evidence connecting metabolic and immune dysregulation to pregnancy loss in PCOS and evaluate novel therapeutic strategies targeting immunometabolic pathways.
CONTENT: This review first presents an overview of the mechanistic pathways implicated in PCOS-related miscarriage, including endocrine-metabolic dysfunction, immune-inflammatory imbalance, oxidative stress and ferroptosis, vascular and coagulation defects, and uterine-placental abnormalities. Both translational and clinical for interventions with dual metabolic-immune effects are highlighted, such as metformin, antioxidants likeN-acetylcysteine, anti-androgens, and combination regimens including aspirin with low-molecular-weight heparin (LMWH). Agents with mechanistic promise but limited exploration, such as glucagon-like peptide-1 (GLP-1) receptor agonists, selenium nanoparticles, and stem cell-based therapies, are also discussed. Future directions for PCOS pregnancy care are outlined, emphasizing the integration of immunometabolic biomarkers, advanced animal models, and mechanism-informed combination trials.
CONCLUSION: PCOS-related miscarriage is increasingly recognized as resulting from dysregulation of immune-metabolic crosstalk. Mechanism-based, multidimensional strategies targeting this dual pathology represent a promising paradigm for preventing and managing pregnancy loss in women with PCOS.

Keywords:  Polycystic ovary syndrome (PCOS); combination therapy; ferroptosis; immunometabolism; miscarriage

DOI:  https://doi.org/10.1080/09513590.2025.2600160
Front Immunol. 2025 ;16 1722080

Immune-mediated mechanisms and maternal-fetal interface dysfunction in obstetric antiphospholipid syndrome.

Guangyu Ma, Jinbiao Han, Rui Gao, Lang Qin.

  Obstetric antiphospholipid syndrome (OAPS) is a complex autoimmune disorder that significantly compromises pregnancy, manifesting as recurrent miscarriage, stillbirth, placental insufficiency, and preeclampsia. Its increasing prevalence underscores the pressing need to elucidate its multifaceted pathogenic mechanisms to improve maternal and fetal outcomes. While traditionally attributed to thrombosis driven by antiphospholipid antibodies (aPL), emerging evidence indicates that OAPS can disrupt placental perfusion, impair trophoblast proliferation and invasion, and compromise placental angiogenesis even in the absence of overt thrombotic events. Beyond direct effects on trophoblasts and vascular remodeling, aPLs profoundly perturb the immune milieu at the maternal-fetal interface, encompassing complement activation, excessive formation of neutrophil extracellular traps (NETs), dysfunction of decidual natural killer cells and macrophages, and dysregulated B cell responses. These immune-mediated alterations collectively establish a sustained pro-inflammatory environment that undermines placental development and predisposes to adverse pregnancy outcomes. This review provides a comprehensive synthesis of the immunopathogenic mechanisms of OAPS that extend beyond thrombosis, and emphasizes the intricate crosstalk between immune cells and the complement-NET axis. A deeper understanding of these immune-mediated pathways may inform the development of targeted therapeutic strategies to optimize maternal and fetal outcomes in affected pregnancies.

Keywords:  antiphospholipid antibodies; immune dysregulation; maternal-fetal interface; obstetric antiphospholipid syndrome; trophoblast dysfunction

DOI:  https://doi.org/10.3389/fimmu.2025.1722080
Gynecol Endocrinol. 2025 Dec 31. 41(1): 2594876

Effect of oral contraceptive pretreatment on IVF outcomes in women with polycystic ovary syndrome using a long GnRH agonist protocol.

Muqing Gu, Xiangyan Ruan, Yanqiu Li, Chanwei Jia, Yinmei Dai.

   OBJECTIVE: To evaluate the effect of oral contraceptive (OC) pretreatment on in vitro fertilization (IVF) outcomes in women with polycystic ovary syndrome (PCOS) undergoing the GnRH agonist (GnRH-a) long protocol, compared with other ovarian stimulation protocols.
METHODS: This retrospective study included 121 women with PCOS, diagnosed according to the Rotterdam criteria, who underwent IVF/intracytoplasmic sperm injection (IVF/ICSI) between January and September 2018 at Beijing Obstetrics and Gynecology Hospital. Patients were assigned to one of four protocols: the OC pretreatment + GnRH-a long protocol (three cycles of OC), the standard GnRH-a long protocol, the GnRH antagonist protocol, or the GnRH-a ultralong protocol. Ovarian stimulation characteristics, embryo development, and clinical outcomes were compared among the groups.
RESULTS: The GnRH-a ultralong protocol required significantly higher total Gn doses and longer stimulation duration than the OC + GnRH-a long protocol. Compared with the standard GnRH-a long protocol, OC pretreatment showed trends toward lower rates of moderate-to-severe ovarian hyperstimulation syndrome (OHSS) and higher biochemical and clinical pregnancy rates, though these differences were not statistically significant. No significant differences were observed among the groups for the number of retrieved oocytes, mature oocytes, fertilized oocytes, or normally developing embryos.
CONCLUSION: In PCOS patients, OC pretreatment showed trends toward higher pregnancy rates and lower OHSS, without adverse effects on clinical outcomes. These findings highlight a potentially promising approach, warranting confirmation in larger, high-quality randomized controlled trials.

Keywords:  Polycystic ovary syndrome; in vitro fertilization; oral contraceptives; ovarian stimulation protocols; pregnancy outcomes

DOI:  https://doi.org/10.1080/09513590.2025.2594876
J Ovarian Res. 2025 Dec 11.

Identifying the mediating role of immune cells on the relationship between plasma lipidomes and PCOS: a two-step Mendelian randomization analysis.

Lidan Liu, Bo Liu, Mujun Li, Lang Qin.

   PURPOSE: Polycystic Ovary Syndrome (PCOS) is a common endocrine disorder, with dysregulated lipid metabolism and immune dysfunction. However, it remains unclear whether immune phenotypes mediate the relationship between lipidomes and PCOS.
METHODS: A two-step Mendelian Randomization analysis was employed to explore the causal relationship between plasma lipidomes and PCOS and to investigate the mediating role of immune cells. A total of 179 plasma lipidomes and 731 immune phenotypes were analyzed. We used single nucleotide polymorphisms (SNPs) associated with plasma lipidome levels as instrumental variables and applied statistical methods, including the inverse-variance weighted approach, to assess potential causal relationships.The function of immune phenotypes in regulating the relationship between lipids and PCOS was evaluated through mediation analysis.
RESULTS: Ten lipid-immune pathways mediating the association between plasma lipidomes and PCOS were identified. Elevated levels of phosphatidylcholines and triacylglycerols increased the risk of PCOS by modulating immune markers such as HLA DR on B cells and CD28 on regulatory T cells. Conversely, phosphatidylinositol (18:1_18:2) demonstrated a protective effect against PCOS through CD33 on myeloid-derived suppressor cells. Six specific plasma lipidomes were causally linked to PCOS risk, including phosphatidylcholine (18:1_20:4) and triacylglycerol (50:4), which increased risk, and phosphatidylinositol (18:1_18:2), which lowered risk. Additionally, 31 immune phenotypes were identified as causally associated with PCOS, with 27 increasing risk and 4 offering protective effects.
CONCLUSION: This study provides evidence that immune phenotypes mediate the relationship between plasma lipidomes and PCOS. These findings highlight the potential of targeting both lipid metabolic processes and immune pathways as novel therapeutic strategies for managing PCOS.

Keywords:  Immune phenotype; Lipidome; Mendelian randomization; Polycystic ovary syndrome (PCOS)

DOI:  https://doi.org/10.1186/s13048-025-01884-z
J Allergy Clin Immunol. 2025 Dec 06. pii: S0091-6749(25)01183-2. [Epub ahead of print]

SEX HORMONES INFLUENCE ORMDL3 EXPRESSION: IMPLICATIONS FOR SEX-ASSOCIATED ASTHMA PHENOTYPE.

Elisabetta Granato, Ida Cerqua, Antonietta Rossi, Maria Antonietta Riemma, Maria Chiara Monti, Giuseppina Ferraro, Barbara Romano, Maria Francesca Nanì, Danilo D'Avino, Martina Simonelli, Joshua Malo, Francesca Polverino, Bruno D'Agostino, Giuseppe Cirino, Fiorentina Roviezzo.

   BACKGROUND: Genetic polymorphisms in sphingolipid metabolism, particularly involving the orosomucoid-like 3 (ORMDL3) gene, have been associated with asthma risk. Notably, asthma prevalence and severity exhibit pronounced sex differences, emerging in childhood and persisting into adulthood. However, the molecular mechanisms underlying this sexual dimorphism remain incompletely elucidated.
OBJECTIVE: To investigate whether ORMDL3 contributes to sex-differences in airway function and asthma-like features.
METHODS: ORMDL3 expression was measured in lung tissues from healthy male and female human donors and in human bronchial epithelial cells (BEAS-2B) following exposure to 17β-estradiol, Dermatophagoides pteronyssinus 1 (Der p 1), or both. A murine preparation of asthma was used to evaluate sex-dependent differences in ORMDL3 expression, airway responsiveness, and remodeling. Pharmacological modulation of estrogen signaling and the ORMDL3-sphingosine-1-phosphate (S1P) axis were employed. Methods included qRT-PCR, immunostaining, Liquid Chromatography coupled to tandem Mass Spectrometry detection (LC-MS/MS), and airway function measurements.
RESULTS: Female lungs exhibited higher ORMDL3 expression than males, and this correlated with elevated forced expiratory volume to forced vital capacity ratios (%FEV1/FVC) in the same patients. In BEAS-2B cells, 17β-estradiol significantly upregulated ORMDL3 and altered sphingolipid metabolism by inducing expression of ceramidase, SphK1/2, and S1P receptors. Der p 1 also increased ORMDL3 and triggered epithelial activation via inflammasome signaling, while estradiol enhanced IFN-β signaling and MUC5AC expression. Combination Derp 1/17β-estradiol synergistically activated sphingolipid, interferon, and inflammasome pathways. These in vitro findings prompted in vivo investigation using a murine asthma preparation, where female mice displayed elevated ORMDL3, sphingosine, and S1P levels, with increased airway hyperresponsiveness (AHR) and remodeling. Treatment with tamoxifen or estradiol normalized AHR and S1P signaling across sexes. Allergen sensitization intensified female-biased ORMDL3 expression and airway inflammation. Inhibition of the ORMDL3-S1P axis attenuated asthma-like features only in females.
CONCLUSION: This study identifies ORMDL3 as an estrogen responsive regulator of airway responsiveness that may contribute to sex-related differences in asthma features through modulation of sphingolipid metabolism.

Keywords:  Airway function; Asthma; ORMDL3; Sex; Sphingolipid metabolism

DOI:  https://doi.org/10.1016/j.jaci.2025.10.035
Poult Sci. 2025 Dec 05. pii: S0032-5791(25)01450-6. [Epub ahead of print]105(1): 106210

17β-estradiol mediates sex-biased progesterone receptor expression via estrogen receptor α in chicken pituitary.

Guixian Bu, Shasha Guo, Li Guo, Yaling Wang, Jingyi Lin, Xinchun Li, Lingyang Li, Linyan Huang, Xianyin Zeng, Jing Feng, Caiyun Sun, Fengyan Meng.

  Sex-biased in gene expression is a pervasive biological phenomenon in animals and plays critical roles in sex-dependent physiological activities. While previous studies have identified numerous genes displaying sex-biased expression at pre- or post-sexual maturity, the regulatory mechanisms driving such differential expression remain poorly understood. Our earlier work showed that progesterone receptor (PGR) expression in the chicken pituitary exhibits sex bias. Herein, we aimed to identify key gonadal steroids and their regulatory mechanisms mediating female-enriched PGR expression in the chicken pituitary. Our results showed that: (1) Pituitary PGR expression in sexually mature chickens was confirmed to be sex-biased; (2) Both in vitro assays and subcutaneous injections demonstrated that 17β-estradiol (E2) potently stimulated PGR expression in the chicken pituitary in a time- and dose-dependent manner, whereas progesterone and dihydrotestosterone showed no such effect; (3) E2-induced PGR transcription relies on estrogen receptor α (ERα) rather than ERβ or G protein-coupled estrogen receptor; (4) Single-cell RNA-seq analysis revealed 26.3 % co-expression of ESR1 (the ERα-encoding gene) and PGR in chicken gonadotrophs; (5) E2-elevated PGR expression may involve both membrane-anchored ERα (mERα)-triggered rapid non-genomic pathways and ERα-associated long-lasting genomic actions; (6) mERα-mediated regulation of pituitary PGR expression in chickens might be linked to PLC-dependent dual messenger systems (IP3/Ca2+ and DAG/PKC), the MEK/ERK cascade, and L-type voltage-gated Ca2+ channels. These findings provide novel insights into the estrogen-dependent regulatory mechanisms of sex-biased PGR expression in the avian pituitary, advancing our understanding of estrogen-mediated modulation of the reproductive axis in birds.

Keywords:  17β-estradiol; Chicken; Estrogen receptor α; Pituitary; Progesterone receptor

DOI:  https://doi.org/10.1016/j.psj.2025.106210
Mol Psychiatry. 2025 Dec 10.

Unraveling sexually dimorphic offspring behaviors: maternal premating stress and the neuro-microbial-metabolic network.

Xiaoyuan Jing, Zhibin Xu, Qixing Yang, Yan Jiang, Jintao Wang, Ruoxi Wang, Yuantao Li, Rouxuan Zhou, Liping Wang, Zuxin Chen, Xin-An Liu.

Psychosocial stress in women is a major public health concern, yet the intergenerational mechanisms linking maternal premating stress to offspring neuropsychiatric vulnerability remain incompletely understood. Here, female mice were exposed to chronic unpredictable mild stress (CUMS) prior to mating, and offspring were assessed for neurodevelopment, adult behavior, and multi-omics profiles. Premating stress induced neurodevelopmental delays and sexually dimorphic adult phenotypes: female offspring exhibited hyperactivity and social deficits, whereas male offspring displayed anxiety. Cerebellum cytokine levels were reduced in a sex-dependent manner. Maternal stress shifted offspring gut microbiota (GM) composition, with p_Proteobacteria as core taxa in females and p_Firmicutes in males, exhibiting sex-dependent and inverse shifts in microbial network connectivity. Male offspring showed marked metabolic alterations and enhanced maternal-offspring metabolic concordance. Integrated analyses of GM, metabolites, and cerebellum profiles identified sexually dimorphic network correlations, further supported by human data demonstrating maternal stress-induced, sex-dependent GM network remodeling. Lactoferrin (LF) intervention selectively rescued male anxiety but not female behavioral deficits, and in males specifically, reduced cerebellum pro-inflammatory cytokines, enhanced GM network connectivity, and enriched immune-related serum metabolic and cerebellum transcriptomic pathways. LF also suppressed Purkinje cell firing frequency in males and reinforced post-treatment connectivity across microbial, metabolic, and cerebellum transcriptional nodes. Collectively, these findings delineate a previously unrecognized sexually dimorphic neuro-microbiota-metabolic network underpinning intergenerational vulnerability and highlight microbiota-targeted modulation as a systems-level mechanistic framework for sex-specific prevention of maternal stress-associated neuropsychiatric disorders.

DOI: https://doi.org/10.1038/s41380-025-03378-2
Biol Sex Differ. 2025 Dec 06.

Sex differences in the blood metabolome of extremely preterm infants: a pilot study on the impact of antibiotic therapy.

Michele Costanzo, Marianna Caterino, Sabrina Bianco, Margherita Ruoppolo, Giovanni Sotgiu, Mariangela Puci, Flavia Franconi, Ilaria Campesi.

   BACKGROUND: Despite growing recognition of sex differences in medicine, little is known about their role in neonatology, particularly among extremely premature infants (EPI, < 28 weeks gestation), who face high morbidity and mortality driven by infections. Antibiotics therapy is widely used but may alter cellular metabolism, leading to adverse drug reactions. However, pharmacological studies in EPI remain limited, and sex-dependent effects of antibiotic treatments are largely unexplored. This study investigated sex-related metabolomic differences in EPI in relation to antibiotic exposure.
METHODS: Targeted mass spectrometry (MS) was applied to dried blood spots (DBS) collected within the neonatal screening program of the Campania region (Italy) between 2018 and 2023. Amino acids (AA) and acylcarnitines (AC) were quantified in 116 EPI stratified by sex and antibiotics treatment.
RESULTS: Untreated EPI of both sexes showed largely comparable metabolic profiles, with the exception of higher C16OH levels in males. Antibiotic treatment, however, markedly amplified sex-dependent divergence, with male EPI displaying significantly elevated AC concentrations (C0, C2, C3, C4, C5, C6, C5OH, C10:1, C16:1, C18, C18:1) compared to females. Stratification by penicillins + aminoglycosides treatment revealed distinct patterns: in EPI treated with a penicillins + aminoglycosides combination, males exhibited higher levels of C0, C2, C4, C6, C16:1, C18, and C18:1, while C3, C5, C5OH, and C10:1 no longer differed by sex. Furthermore, eight additional AC (C3DC, C14:1, C14, C16, C10DC, C16OH, C4OH, C16:1OH) were significantly elevated in treated males, differences that were not detected when all antibiotic classes were pooled.
CONCLUSIONS: These findings demonstrate that standard empirical antibiotic therapies for prematurity exert sex-dependent effects on neonatal metabolism, with antibiotics amplifying AC alterations in males. Our results underscore the need to consider sex as a key biological variable in neonatal pharmaco-metabolomics and highlight the potential of metabolic profiling to optimize individualized treatments in EPI.

Keywords:  Antibiotics; Blood metabolomics; Extremely preterm infants; Sex differences

DOI:  https://doi.org/10.1186/s13293-025-00798-1