bims-simsho 2025-08-03 papers

bims-simsho

Biomed News

on Systems immunology and sex hormones

Issue of 2025–08–03
sixteen papers selected by
Chun-Chi Chang, Lunds universitet

Immunological Factors in Recurrent Pregnancy Loss: Mechanisms, Controversies, and Emerging Therapies.
The Interaction Between Sex and Thyroid Cancer Development and Management.
Sex Bias in Autoimmunity: New Findings and New Opportunities.
Sex differences in inflammation and markers of gut integrity in long COVID.
Prevalence and Metabolic Characterization of Polycystic Ovary Syndrome in a Cohort of Patients Diagnosed with Spina Bifida: Study Protocol.
The influence of vaginal microbiota on ewe fertility: a metagenomic and functional genomic approach.
Role of AMP-Activated Protein Kinase (AMPK) in Female Reproduction: A Review.
Exploring the role of microbiota in mediating sexually dimorphic infection outcomes in mealworm beetles.
Factors Affecting IVF Success after Laparoscopic Surgery in Women with Endometriosis.
Epigenetic priming as a driver of memory recall and dysfunction in T cells.
BCG Vaccination Potentially Modulates the Transcriptome of Infant CD4 T Cells in Addition to Age-Dependent Immune Ontogeny-Associated Changes.
Identification and validation of biomarkers associated with glycolysis in polycystic ovarian syndrome.
Tissue-specific metabolomic signatures for a doublesex model of reduced sexual dimorphism.
Glucose absorption in the duodenum is modulated by an estrogen receptor α-dependent regulation of glucose transporter functional expression.
Sex-specific DNA methylation associations with circulating urate levels and BCG-induced urate changes.
Early-life human CD8+ T cells exhibit rapid, short-lived effector responses and a unique transcription factor landscape.

Biology (Basel). 2025 Jul 17. pii: 877. [Epub ahead of print]14(7):

Immunological Factors in Recurrent Pregnancy Loss: Mechanisms, Controversies, and Emerging Therapies.

Efthalia Moustakli, Anastasios Potiris, Athanasios Zikopoulos, Eirini Drakaki, Ioannis Arkoulis, Charikleia Skentou, Ioannis Tsakiridis, Themistoklis Dagklis, Peter Drakakis, Sofoklis Stavros.

  Immunological factors have gained growing recognition as key contributors to recurrent pregnancy loss (RPL) after in vitro fertilization (IVF), representing a major challenge in reproductive medicine. RPL affects approximately 1-2% of women trying to conceive naturally and up to 10-15% of those undergoing IVF, where overall success rates remain around 30-40% per cycle. An imbalance in maternal immunological tolerance toward the semi-allogeneic fetus during pregnancy may lead to miscarriage and implantation failure. IVF-related ovarian stimulation and embryo modification offer additional immunological complications that can exacerbate existing immune dysregulation. Recent advances in reproductive immunology have significantly deepened our understanding of the immune mechanisms underlying RPL following IVF, particularly highlighting the roles of regulatory T cells (T regs), natural killer cells, cytokine dysregulation, and disruptions in maternal-fetal immune tolerance. In order to better customize therapies, this evaluation incorporates recently discovered immunological biomarkers and groups patients according to unique immune profiles. Beyond conventional treatments like intralipid therapy and intravenous immunoglobulin, it also examines new immunomodulatory medications that target certain immune pathways, such as precision immunotherapies and novel cytokine modulators. We also discuss the debates over immunological diagnostics and therapies, such as intralipid therapy, intravenous immunoglobulin, corticosteroids, and anticoagulants. The heterogeneity of patient immune profiles combined with a lack of strong evidence highlights the imperative for precision medicine to improve therapeutic consistency. Novel indicators for tailored immunotherapy and emerging treatments that target particular immune pathways have encouraging opportunities to increase pregnancy success rates. Improving management approaches requires that future research prioritize large-scale clinical trials and the development of standardized immunological assessments. This review addresses the immunological factors in RPL during IVF, emphasizing underlying mechanisms, ongoing controversies, and novel therapeutic approaches to inform researchers and clinicians.

Keywords:  assisted reproductive technologies (ART); cytokines; emerging therapies; immunological factors; recurrent pregnancy loss (RPL)

DOI:  https://doi.org/10.3390/biology14070877
Endocrinol Metab Clin North Am. 2025 Sep;pii: S0889-8529(25)00038-6. [Epub ahead of print]54(3): 483-495

The Interaction Between Sex and Thyroid Cancer Development and Management.

Farah I Kitana, Leila Shobab.

  This article explores the sex difference in incidence and progression of differentiated thyroid cancer (DTC). The article examines epidemiologic studies highlighting sex disparities in survival rates between men and women, with women experiencing a more favorable prognosis before menopause. It also discusses the role of sex hormones, genetic and epigenetic factors, and the immune system as potential contributors to the underlying mechanism of sex difference in DTC. The article advocates for sex-specific research to better understand the molecular mechanisms behind these observed sex differences and to develop targeted, sex-specific, and more individualized therapies for advanced, radioactive iodine refractory thyroid cancer.

Keywords:  Estrogen receptor in thyroid cancer; Sex bias in thyroid cancer; Sex difference in thyroid cancer; Sex hormones and thyroid cancer

DOI:  https://doi.org/10.1016/j.ecl.2025.03.016
JID Innov. 2025 Sep;5(5): 100391

Sex Bias in Autoimmunity: New Findings and New Opportunities.

Vincent van Drongelen, Joanna Rew, Allison C Billi.

  Autoimmune diseases result from the immune system's inability to discriminate between self and foreign antigens, leading to development of self-reactive immune cells and autoantibodies that can cause organ damage and failure. It has long been known that many autoimmune diseases are more common in females. Although much progress has been made over the years, the exact mechanisms for this sex bias are not yet fully understood. In this review, we provide an overview and update on how chromosomes, genes, sex hormones (including gender-affirming hormone therapy), immunometabolism, and the skin can play a role in sex-biased autoimmunity. We also identify gaps in our understanding that require additional research. In an era of increased development of personalized medicine, a thorough understanding of sex bias in autoimmunity may facilitate the development of much-needed targeted therapeutics, thereby reducing the risks of broader immunosuppression and adverse effects that lead to premature termination of treatment by patients.

Keywords:  Autoimmunity; Sex

DOI:  https://doi.org/10.1016/j.xjidi.2025.100391
Sci Rep. 2025 Jul 28. 15(1): 27374

Sex differences in inflammation and markers of gut integrity in long COVID.

Jared C Durieux, Ziad Koberssy, Joviane Daher, Jhony Baissary, Marc Abboud, Ornina Atieh, Christopher Woolverton, Grace A McComsey.

  Endothelial damage represents an essential pathogenic mechanism of respiratory and multiorgan dysfunction as seen in the post-acute phase of COVID-19. Biological differences between male and female sex, inflammation, and gut integrity may have an integral role in endothelial damage and explain the residual effects of COVID-19 infection in long COVID, yet evidence is limited. Confirmed COVID-19 negative participants were 1:1 propensity-score matched to COVID-19 positive participants. Symptoms occurring at least one-month following COVID-infection and lasting more than three-months was defined as long COVID. Measures of endothelial function included reactive hyperemic index (RHI ≥ 1.67 = normal endothelial function) and augmentation index (higher AIx = worse arterial elasticity). A total of 89 COVID-19 negative participants was matched to 89 COVID-19 positive participants. Among the COVID-19 survivors, the median age was 42.92 years, 46.07% were female sex, and 57 (64%) had long COVID. Higher levels of inflammation (TNF-RI and oxLDL) and gut integrity (zonulin and BDG) was associated (P < 0.05) with a two-fold increase in the odds of long COVID. Female sex, independent of COVID-19 status, was 4x more likely to have worse AIx (P < 0.0001) compared to male sex. Among female sex with long COVID, higher levels of inflammation (IL-6, VCAM, hsCRP) and gut integrity (zonulin) was independently associated (P < 0.05) with higher AIx. Female sex with long COVID symptoms had the worse inflammation, gut integrity, and arterial stiffness among COVID-19 survivors. This reinforces the importance of continued, long-term follow-up care following COVID-19 infection, with special attention needed for female sex who may be at a higher cardiovascular disease risk.

Keywords:  Arterial stiffness; COVID-19; Endothelial dysfunction; Gut integrity; Inflammation; Long COVID; Long COVID symptoms; Sex differences

DOI:  https://doi.org/10.1038/s41598-025-11470-4
Children (Basel). 2025 Jun 27. pii: 851. [Epub ahead of print]12(7):

Prevalence and Metabolic Characterization of Polycystic Ovary Syndrome in a Cohort of Patients Diagnosed with Spina Bifida: Study Protocol.

Giorgio Sodero, Clelia Cipolla, Federica Arzilli, Claudia Rendeli.

  Background: Myelomeningocele, commonly known as spina bifida, is a congenital malformation of the spinal cord. Polycystic ovary syndrome (PCOS) is a complex endocrine-metabolic disorder affecting 9-21% of women of reproductive age and is characterized by hyperandrogenism and ovulatory dysfunction. Hyperhomocysteinemia, insulin resistance, metabolic syndrome, and alterations in inositol metabolism play a crucial pathophysiological role in both PCOS and spina bifida; however, the potential link between these two significant conditions has not been explored. Objectives: The primary objective of our study is to assess the prevalence of PCOS among female pediatric patients with a prior diagnosis of spina bifida. Additionally, we will evaluate differences in auxological and metabolic parameters between patients diagnosed with PCOS and those without the diagnosis. The secondary objectives of our study include the following: characterizing the metabolic profiles of patients with PCOS and differentiating between various phenotypic forms of PCOS. Methods: Prospective, cross-sectional, observational, and monocentric study. The study will have an overall duration of 24 months, with the potential for extension until the last patient is enrolled. The recruitment period is set at 12 months.

Keywords:  pediatric endocrinology; pediatric urology; polycystic ovary syndrome; spina bifida

DOI:  https://doi.org/10.3390/children12070851
Microbiome. 2025 Aug 01. 13(1): 177

The influence of vaginal microbiota on ewe fertility: a metagenomic and functional genomic approach.

Edgar L Reinoso-Peláez, María Saura, Carmen González, Manuel Ramón, Jorge H Calvo, Magdalena Serrano.

   BACKGROUND: Despite advancements in artificial insemination, sheep fertility rates remain suboptimal. Recent studies in other species highlight the critical role of reproductive microbiota in influencing fertility outcomes. This research explores the relationship between ovine vaginal microbiota, associated functional pathways, and fertility using advanced nanopore long-reading metagenomic sequencing on 297 ewes from three Spanish breeds across four herds. The study aimed to describe a core vaginal microbiota, analyse the complex interactions with herd, breed, age, and parity factors, and identify taxa and genes associated with reproductive success by artificial insemination.
RESULTS: The study identified Staphylococcus, Escherichia, and Histophilus as the most abundant genera. Microbial communities varied considerably between breeds and herds, with high predictive accuracy (> 90%) in classification models. Differential abundance analysis revealed that the genera Histophilus, Fusobacterium, Bacteroides, Campylobacter, Streptobacillus, Gemella, Peptoniphilus, Helococcus, Treponema, Tissierella, and Phocaeicola were more abundant in non-pregnant ewes. Some of these taxa were also associated with four COG entries and one KEGG orthologue significantly linked to non-pregnancy, primarily involving carbohydrate metabolism, defence mechanisms, and structural resilience. Age and parity were also associated with microbiota composition, particularly in ewes older than five years or with more than three parturitions, suggesting that cumulative physiological changes may contribute to microbial shifts over time.
CONCLUSIONS: The ewe's vaginal microbiome appears to be mainly influenced by both herd and breed, though distinguishing genetic from environmental factors is challenging within our study design. While the overall microbiota showed a subtle effect on pregnancy, certain genera had a significant negative impact, likely due to pathogenic or inflammatory properties that disrupt reproductive health. The metagenomic approach used here enabled not only comprehensive taxonomic classification but also detailed functional analysis, providing deeper insights into the microbiome's role in reproductive outcomes. Video Abstract.

Keywords:  Artificial insemination; Fertility; Metagenomics; Microbiome; Microbiome-wide prediction; Ovine; Random forest; Reproductive success; Vaginal microbiota

DOI:  https://doi.org/10.1186/s40168-025-02165-z
Int J Mol Sci. 2025 Jul 16. pii: 6833. [Epub ahead of print]26(14):

Role of AMP-Activated Protein Kinase (AMPK) in Female Reproduction: A Review.

Nurul Ain Kamar Bashah, Adila A Hamid, Siti Hajar Adam, Farah Hanan Fathihah Jaffar, Izzat Zulhilmi Abd Rahman, Mohd Helmy Mokhtar.

  The adenosine monophosphate (AMP)-activated protein kinase (AMPK) signalling pathway regulates cell metabolism, inflammation and the immune response. This signalling pathway is essential for maintaining reproductive homeostasis and influencing steroidogenesis, implantation, and embryonic development. The central sensor, AMPK, regulates cell function in response to metabolic stress. The dysregulation of AMPK signalling has been implicated in several female reproductive disorders, including polycystic ovary syndrome (PCOS), endometriosis, infertility, and reproductive ageing. This review provides an overview of the role of AMPK in reproductive function and disorders, as well as potential therapeutic targets to restore balance in this signalling pathway. It discusses AMPK signalling in folliculogenesis, oocyte maturation, pregnancy maintenance, pre-eclampsia (PE) pathogenesis, PCOS, preterm birth, endometriosis, dysmenorrhoea and other disorders related to female reproduction. A deeper understanding of AMPK signalling in these contexts could provide new insights for the development of therapeutic interventions for reproductive health.

Keywords:  AMP-activated protein kinase (AMPK); folliculogenesis; polycystic ovarian syndrome; pre-eclampsia; pregnancy

DOI:  https://doi.org/10.3390/ijms26146833
Biol Lett. 2025 Jul;21(7): 20250136

Exploring the role of microbiota in mediating sexually dimorphic infection outcomes in mealworm beetles.

Srijan Seal, Devashish Kumar, Pavankumar Thunga, Pawan Khangar, Manisha Gupta, Dipendra Nath Basu, Rhitoban Raychoudhury, Imroze Khan.

  Sexually dimorphic responses to pathogenic infections in animals may stem from sex-specific differences in their life history and immune investment. Recent evidence highlights that such sex-specific variations in immune responses can also be critically regulated by the microbiota. However, direct experiments to test how the microbiota jointly impacts sex-specific immunity and vulnerability to pathogens are still limited. To this end, we used Tenebrio molitor beetles to first establish that the sexes appear to differ in their microbiota composition and infection responses. Females were more vulnerable to bacterial infections and carried a higher bacterial load than males. When we depleted the microbiota, only females improved their post-infection survival, leading to a decrease in the level of sex-specific divergence in infection outcomes. Males, on the other hand, remained unaffected. Microbiota recolonization (via feeding on faecal matter) of microbiota-depleted females increased their susceptibility to infection again, restoring the strong sexual dimorphism. We thus found a potential association between microbiota and infection responses. We also found reduced expression of an antimicrobial peptide, tenecin 1, in females, which could be associated with their higher infection susceptibility, but such immune gene versus phenotypic associations were not consistent across microbiota manipulations. Immune strategies that are required to mediate the plausible links between microbiota and infection response might thus vary with microbiota manipulations, warranting future investigations.

Keywords:  Tenebrio molitor; immunity; infection susceptibility; microbiota; sexual dimorphism

DOI:  https://doi.org/10.1098/rsbl.2025.0136
Med J Islam Repub Iran. 2025 ;39 61

Factors Affecting IVF Success after Laparoscopic Surgery in Women with Endometriosis.

Abolfazl Mehdizadehkashi, Shahla Chaichian, Roya Derakhshan, Farahnaz Farzaneh, Azam Govahi, Azar Mohammadzadeh, Banafsheh Nikfar, Yasaman Kabir Anaraki.

   Background: Considering low-quality evidence regarding the impact of laparoscopic surgery on in vitro fertilization (IVF) success rates in women with endometriosis, our research aimed to evaluate IVF success rates and their influential factors in women with endometriosis-related infertility who underwent laparoscopic surgery.
Methods: In a retrospective cohort study, we included women aged 15 to 40 years diagnosed with endometriosis-related infertility who underwent laparoscopic surgery in a university hospital. Women with severe male factor infertility, adenomyosis, uterine myomas, premature ovarian insufficiency, incomplete information, or inaccessible data from infertility centers were excluded. Data were collected from the Endometriosis Data Registry approved by the Iran University of Medical Sciences under code number 1400-2-65-21233, including age, body mass index, infertility duration, endometriosis severity, and Anti-Müllerian hormone levels before IVF. IVF success was considered by an embryonic heartbeat identification during an ultrasound exam, that is, a clinical pregnancy. Independent sample t test, Mann-Whitney, and chi-square tests were applied for single-variable analysis, and logistic regression was used for multivariable analysis.
Results: Of 55 eligible patients, IVF was successful in 23 (41.81%). The mean age of participants was 34.98 years, with a standard deviation of 5.93 years. Endometriomas were observed in 42 (76%) of the participants; unilateral endometriomas were more common than bilateral (25 [45.5%] vs 17 [30.9%]). No significant differences were identified between the IVF-positive and IVF-negative groups regarding clinical and demographic characteristics.
Conclusion: Laparoscopic surgery in women with deep infiltrating endometriosis enhances IVF success and increases pregnancy rate.

Keywords:  Assisted Reproductive Technique; Endometriosis; In Vitro Fertilization; Infertility; Laparoscopy

DOI:  https://doi.org/10.47176/mjiri.39.61
J Exp Med. 2025 Sep 01. pii: e20241433. [Epub ahead of print]222(9):

Epigenetic priming as a driver of memory recall and dysfunction in T cells.

Mieke Metzemaekers, Niels J Rinzema, Ralph Stadhouders.

T cells are essential for protective immunity against pathogens and malignancies. While the initial activation of a naive T cell is slow, antigen-experienced or memory T cells mount near-immediate protective responses through their remarkable capacity to instantaneously reactivate inflammatory gene programs upon antigen rechallenge. Evidence is emerging that this immunological memory is underpinned by dynamic changes at the chromatin level or epigenome of T cells. Here, we review recent findings on how epigenetic mechanisms are a driving force guiding initial T cell activation and differentiation, and durably endow memory T cells with the ability to remember gene regulatory processes essential for high-magnitude protective immune responses. We discuss the molecular programs that may be involved in the establishment and maintenance of chromatin-based information in memory T cells during homeostasis, and how undesired epigenetic priming may program T cells for dysfunction in patients with chronic immune-related disease and cancer.

DOI: https://doi.org/10.1084/jem.20241433
Vaccines (Basel). 2025 Jun 29. pii: 706. [Epub ahead of print]13(7):

BCG Vaccination Potentially Modulates the Transcriptome of Infant CD4 T Cells in Addition to Age-Dependent Immune Ontogeny-Associated Changes.

Vidya Vijayan Karuvan Kandiyil, Eunchong Kang, Emily Coates, Portia Kamthunzi, Gerald Tegha, Mina Hosseinipour, Di Wu, Fei Zou, Kristina De Paris.

   BACKGROUND: The Bacille Calmette-Guérin (BCG) vaccine is part of the Extended Programme on Immunization (EPI) and as such is generally administered at birth. The global introduction of BCG not only protected many vaccinated infants against severe complications of tuberculosis but also resulted in markedly reduced overall childhood mortality. Studies in human adults determined that BCG vaccination induces epigenetic reprogramming of innate immune cells (also known as trained immunity) and can also enhance T cell responses to both mycobacterial and non-mycobacterial antigens.
GOAL AND METHODS: The current study tested the hypothesis that BCG immunization similarly impacts the functionally distinct infant immune system. Towards this goal, we applied RNA sequencing to assess transcriptome changes in circulating CD4+ T cells of Malawian infants prior to and 2 to 13 weeks after BCG immunization.
RESULTS: In the first three months of life, transcriptome changes of infant CD4 T cells implied a functional shift towards T helper 1 and Th17 immunity. Vaccination with BCG resulted in additional modulation of the CD4 T cell transcriptome and differentially expressed genes could be linked to metabolomic function.
CONCLUSIONS: These findings are consistent with data reported in BCG vaccinated adults and contribute to the understanding of molecular changes in infant CD4 T cells that may explain the improved capacity of the infant immune system to respond to pathogens after BCG vaccination.

Keywords:  BCG vaccination; immune ontogeny; infant CD4 T cell transcriptome; signaling pathways

DOI:  https://doi.org/10.3390/vaccines13070706
Sci Rep. 2025 Jul 26. 15(1): 27199

Identification and validation of biomarkers associated with glycolysis in polycystic ovarian syndrome.

Rongyan Zhu, Xiao Yu, Yulan Li.

  Polycystic ovary syndrome (PCOS), an endocrine disorder emerging in adolescence and reproductive years, has been linked to glycolysis in prior studies, though the precise mechanistic role of glycolysis in its pathogenesis remains unclear. Therefore, this study sought to identify glycolysis-related biomarkers in PCOS and elucidate their regulatory mechanisms to provide novel therapeutic strategies. Utilizing publicly available datasets, biomarkers were identified via differential analysis, various PPI algorithms, and validation of expression patterns. Subsequent analyses included functional enrichment, tissue and cell-specific expression profiling, m6A modification site prediction, compound screening, molecular network construction, and molecular docking. RT-qPCR was performed on clinical samples for experimental validation. Two biomarkers, TXNIP and TGFBI, were identified and jointly enriched in "complement and coagulation cascades". TXNIP showed elevated expression in tongue and endocrine cells, whereas TGFBI was highly expressed in placental and adipocyte tissues. TGFBI had 14 high-confidence m6A modification sites and TXNIP had 1 high-confidence m6A modification site. The identified regulatory networks included hsa-miR-6761-5p-TXNIP-PPARG and hsa-miR-6761-5p-TGFBI-RB1. Four key compounds-acetaminophen, bisphenol A, tetrachlorodibenzodioxin, and valproic acid-were prioritized, with molecular docking revealing strongest binding affinities between bisphenol A and both biomarkers (TXNIP: -5.9 kcal/mol; TGFBI: -13.1 kcal/mol). RT-qPCR validation in granulosa cells from PCOS patients confirmed significant upregulation of TGFBI and TXNIP, aligning with bioinformatics predictions. These findings suggest that TXNIP and TGFBI may serve as potential biomarkers associated with glycolytic dysregulation in PCOS, offering insights into the interplay between metabolic dysfunction and disease mechanisms.

Keywords:  Biomarkers; Glycolysis; Polycystic ovary syndrome; TXNIP

DOI:  https://doi.org/10.1038/s41598-025-11591-w
R Soc Open Sci. 2025 Jul;12(7): 250770

Tissue-specific metabolomic signatures for a doublesex model of reduced sexual dimorphism.

Rene Coig, Benjamin Harrison, Richard Johnson, Michael J MacCoss, Daniel Promislow.

  Sex has a major effect on the metabolome. However, we do not yet understand the degree to which differences in metabolism are associated with anatomical dimorphism and modulated by sex-specific tissues. In the fruit fly, Drosophila melanogaster, knocking out doublesex (dsx) gives rise to adults with intermediate sex characteristics. Here, we sought to determine the degree to which this key node in sexual development leads to sex differences (SD) in the metabolome. We measured 91 metabolites across three tissues, comparing sex-dimorphic flies with those of reduced dimorphism: dsx null flies. The abundance of 51% of metabolites (46/91) differed between wildtype XX and XY flies in at least one tissue. However, in dsx flies, we only observed a sex difference in kynurenate, suggesting that dsx plays a major role in SD in fly metabolism. Kynurenate was consistently higher in XX flies in both dsx flies and controls. We also observed tissue-specific effects in dsx flies. Sex dimorphism manifests in part through dimorphic growth of organs, and we find that dimorphic metabolites across the fly enriched the growth-related branched-chain amino acid and mammalian target of rapamycin pathways. Our findings demonstrate that sex dimorphism is accompanied by substantial effects on the metabolome throughout the body.

Keywords:  Doublesex; Drosophila melanogaster; metabolomics; sex differences; sexual dimorphism

DOI:  https://doi.org/10.1098/rsos.250770
BMJ Open Diabetes Res Care. 2025 Jul 27. pii: e004914. [Epub ahead of print]13(4):

Glucose absorption in the duodenum is modulated by an estrogen receptor α-dependent regulation of glucose transporter functional expression.

Jianhong Ding, Xiaoxu Yang, Weixi Shan, Jingyu Xu, Qian Du, Changmei Chen, Qiushi Liao, Jun Lou, Zhe Jin, Mingkai Chen, Rui Xie.

   INTRODUCTION: The mechanisms of estrogen in glucose metabolism are well established; however, the role of this hormone in glucose absorption remains unclear. In this study, we investigated the effects of estrogen on glucose absorption in humans, mice, and the human intestinal epithelium cell line SCBN.
RESEARCH DESIGN AND METHODS: The ovariectomized (OVX) animal model was established. Radioimmunoassay was used to detect the serum estradiol level. Blood insulin, glucose, and homeostatic model assessment of insulin resistance index were determined. Oral glucose tolerance test was used to detect the glucose tolerance of OVX mice and women aged 20-30 years. Ussing chamber experiments were performed to measure glucose absorption ex vivo in the duodenum of the mice. Western blot and immunohistochemistry were used to detect the expressions of estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), sodium/glucose cotransporter 1 (SGLT1), glucose transporter 2 (GLUT2), phosphorylated protein kinase C (PKC), p75 neurotrophin receptor and cluster of differentiation 36.
RESULTS: In women aged 20-30 years, we first observed a correlation between estrogen and blood glucose, with lower glucose tolerance in the premenstrual phase compared with the preovulatory phase. Similarly, compared with the controls, OVX mice showed increased body weight and abdominal fat, decreased levels of serum estradiol, and reduced duodenal (1) expression ERα and ERβ, (2) expression of SGLT1 and GLUT2, and (3) glucose absorption. In SCBN cells, estrogen upregulated SGLT1 and GLUT2 expression; silencing of ERα, but not ERβ, reversed this trend, suggesting that ERα is a key regulator. Mechanistically, estrogen modulates PKC signaling downstream.
CONCLUSIONS: Our findings suggest that, at least in premenopausal women and female mice, glucose absorption is in part regulated by estrogen via an ERα-dependent modulation of the functional expression of SGLT1 and GLUT2 in the duodenum.

Keywords:  Estrogen; Glucose Absorption

DOI:  https://doi.org/10.1136/bmjdrc-2025-004914
Commun Med (Lond). 2025 Jul 31. 5(1): 321

Sex-specific DNA methylation associations with circulating urate levels and BCG-induced urate changes.

Zhaoli Liu, Tania O Crișan, Cancan Qi, Manoj Kumar Gupta, Xuan Liu, Simone J C F M Moorlag, Valerie A C M Koeken, Xun Jiang, Mohamad Ballan, L Charlotte J de Bree, Vera P Mourits, Xu Gao, Andrea Baccarelli, Joel Schwartz, Frank Pessler, Carlos A Guzmán, Yang Li, Mihai G Netea, Leo A B Joosten, Cheng-Jian Xu.

BACKGROUND: Urate concentration and the physiological regulation of urate homeostasis exhibit clear sex differences. DNA methylation has been shown to explain a substantial proportion of serum urate variance, mediate the genetic effect on urate concentration, and co-regulate with cardiometabolic traits. However, whether urate concentration is associated with DNA methylation in a sex-dependent manner is unknown. Additionally, it is worth investigating if urate changes after perturbations, such as vaccination, are associated with DNA methylation in a sex-specific manner.
METHODS: We investigated the association between DNA methylation and serum urate concentrations in a Dutch cohort of 325 healthy individuals. Urate concentration and DNA methylation were measured before and after Bacillus Calmette-Guérin (BCG) vaccination, used as a perturbation associated with increased gout flares. The association analysis included united, interaction, and sex-stratified analysis.
RESULTS: 215 CpG sites are associated with serum urate in males, while 5 CpG sites are associated with serum urate in females, indicating sex-specific associations. Circulating urate concentrations significantly increase after BCG vaccination, and baseline DNA methylation is associated with differences in urate concentration before and after vaccination in a sex-specific manner. The CpG sites associated with urate concentration in males are enriched in neuro-protection pathways, whereas in females, the urate change-associated CpG sites are related to lipid and glucose metabolism.
CONCLUSIONS: Our study enhances the understanding of how epigenetic factors contribute to regulating serum urate levels in a sex-specific manner. These insights highlight the importance of personalized and sex-specific approaches in medicine.

DOI: https://doi.org/10.1038/s43856-025-01044-w
Proc Natl Acad Sci U S A. 2025 Aug 05. 122(31): e2421106122

Early-life human CD8+ T cells exhibit rapid, short-lived effector responses and a unique transcription factor landscape.

Nina N Brodsky, Monisha Chakder, Dinesh Babu Uthaya Kumar, Anis Barmada, Julia Wang, Weihong Gu, Oluwabunmi Olaloye, Anjali Ramaswamy, Aanchal Wats, Liza Konnikova, Carrie L Lucas.

  Neonates and infants are distinct in their clinical and cellular responses to viral infections, with neonatal CD8+ T cells displaying innate-like characteristics and a low threshold for T cell receptor activation. However, specific molecular programs that drive these unique responses are incompletely understood, particularly in humans, and targetable pathways to modulate viral illness in this vulnerable population remain to be elucidated. Early-life immune responses may be developmentally programmed to prioritize avoidance of tissue immunopathology, especially while maternal immunoglobulin provides passive immunity. We set out to define the unique response characteristics and transcription factor landscape of neonatal human CD8+ T cells. Here, we report evidence that naïve neonatal human CD8+ T cells are poised for an accelerated effector switch, with elevations of killer cell lectin-like receptor G1 (KLRG1), killer cell lectin-like receptor B1 (KLRB1/CD161), Fc epsilon receptor I-gamma (FCER1G), DNAX accessory molecule-1 (DNAM1/CD226), granzymes, tumor necrosis factor alpha (TNFα), interleukin 2 (IL-2), and glycolysis compared to naïve adult CD8+ T cells. Further, rapid proliferation and cell death occur upon activation of neonatal CD8+ T cells, with cell viability largely rescued by IL-2 or IL-7. These features are coupled with a unique transcription factor landscape, including high expression of thymocyte selection associated high mobility group box (TOX) and HELIOS (IKZF2), and these signatures continue in postnatal life until at least 2 mo of age. We conclude that early-life human CD8+ T cells maintain a unique transcriptional state associated with an accelerated effector switch and short-lived effector program, revealing key nodes of regulation relevant for the unique immunobiology of neonatal humans.

Keywords:  CD8+ T cell; differentiation; effector; neonate; transcription factor

DOI:  https://doi.org/10.1073/pnas.2421106122