bims-simsho Biomed News
on Systems immunology and sex hormones
Issue of 2026–01–25
forty papers selected by
Chun-Chi Chang, Lunds universitet
  1. The X Factor in Immunity: Sex Differences Shaped by the X Chromosome.
  2. Sex Differences in the Impact of Obesity on Immunity.
  3. Sex matters: mechanistic insights into sex-driven patterns of autoimmunity and implications for pharmacotherapy.
  4. Ovarian Hormones and Obesity Drive Th17-mediated Airway Inflammation through Estrogen Receptor Signaling.
  5. Hormonal and metabolic profiles in teenagers and young adults with polycystic ovary syndrome (PCOS).
  6. Inhibition of estrogen receptor alpha stabilizes regulatory T cell function in autoimmune hepatitis.
  7. Reproductive toxicity of endosulfan: Mechanisms and impacts on female and male reproductive health.
  8. Sex-specific effects of peptidyl arginine deiminase 4 deficiency in the cafeteria diet-induced obesity-associated metabolic complications.
  9. Androgen receptor contributes to radioresistance through DNA repair and autophagy in AR-positive prostate cancer cells.
  10. Genetic, endocrine and epigenetic mechanisms underlying sexual size dimorphism in fish.
  11. Integrated transcriptomic and proteomic profiling identifies an interferon-dependent inflammatory endotype in sepsis.
  12. Beyond XX and XY, Understanding Sex Differences in Leukemia.
  13. Placental aberrant inflammation and spatial-specific lipid metabolism contribute to hypertensive disorder of pregnancy susceptibility in preeclampsia offspring.
  14. Blood Cell Mitochondrial Respiration Increases With Age and Varies by Sex in Healthy Adults.
  15. Western lifestyle linked to maladaptive trained immunity.
  16. Dihydrotestosterone binding to the androgen receptor inhibits apoptosis in ovine undifferentiated granulosa cells via AMH signaling.
  17. Clinical features and genetic analysis of androgen receptor gene variants in 30 prepubertal patients with androgen insensitivity syndrome.
  18. NCOA1 is a gatekeeper of the sexually dimorphic thermogenic activity of white adipose tissue.
  19. Growing up in comfort: Environmental enrichment shapes maternal approach and sex differences in offspring neuroendocrine profiles in laboratory mice.
  20. Gut microbiome composition influences immunologic alterations in the blood and gut of HIV-positive and HIV-negative men who have sex with men.
  21. Why sex and gender matter in cancer research and care.
  22. Exploring the impact of age, sex and life experiences on plasma inflammatory profiles through comparative proteomics.
  23. Spatiotemporal regulation of energetic charge dictates T cell function.
  24. Integrative transcriptomic profiling reveals subtype-specific therapeutic vulnerabilities and resistance mechanisms in prostate cancer.
  25. Commensal microbe-derived butyrate enhances T follicular helper cell function to boost mucosal vaccine efficacy.
  26. The influence of immune regulation mediated by intestinal microbiota on postmenopausal osteoporosis and intervention strategies.
  27. Sex differences in ECGs of trained athletes: A systematic review and meta-analysis.
  28. Luteinizing Hormone β-subunit Gene Polymorphisms and Androgen Levels are Less Predictive of Ovarian Response in Polycystic Ovary Syndrome In vitro Fertilisation Women: A Nested Case-Control Study.
  29. Decidual stromal cells drive CD16+ macrophages towards an immunoregulatory phenotype via extracellular matrix-adhesion molecule interaction during early pregnancy.
  30. Identifying androgen receptor antagonists using a metabolically competent high-throughput screening assay.
  31. Regnase-1 in cDC1 controls T cell priming and shapes the dynamics of experimental autoimmune encephalomyelitis.
  32. Correlation between ambulatory blood pressure indices and sex hormone imbalance in hypertensive women with different menopausal durations: a cross-sectional study.
  33. Women with polycystic ovary syndrome exhibit impaired endometrial receptivity with excessive ERα and histone lactylation.
  34. Single nuclei and spatial profiling of sacrococcygeal teratomas reveals cellular composition and X inactivation heterogeneity.
  35. IL-18 produced by pregnant uterus promotes essential inflammatory responses and fetoplacental growth.
  36. Gut Microbiota Changes After Hormonal or Surgical Treatment for Endometriosis.
  37. A sexually dimorphic neuronal cluster in the mouse medial amygdala responds to male sexual status.
  38. Vaginal Lactobacillus postbiotics ameliorate Gardnerella vaginalis-induced bacterial vaginosis by regulating vaginal microbiota and restoring Th17/Treg balance.
  39. Maternal microbiota and its potential implications for mammalian reproduction health.
  40. Early-life microbiota skews long-term gene expression and chromatin states of bone marrow hematopoietic precursors.
  1. Immunol Rev. 2026 Mar;338(1): e70107
    The X Factor in Immunity: Sex Differences Shaped by the X Chromosome.
    Katherine B Radovanovic, Megan Wynalda, Montserrat C Anguera.
      There are sex differences with immune responses where females exhibit stronger immune responses compared to males. Both sex hormones and sex chromosome differences between males and females contribute to the observed sex differences with innate and adaptive immune cell composition and function. Here, we present recent findings investigating sex differences with immune cells and responses, highlighting contributions from sex hormones or X-linked genes. We also review the epigenetic gene regulatory mechanisms that form the inactive X chromosome (Xi), known as X-Chromosome Inactivation (XCI), the heterochromatic nature of the Xi that allows for selective gene reactivation, and recent work investigating the mechanisms of XCI maintenance in female immune cells. We also highlight some dosage-sensitive X-linked genes involved in female-biased autoimmune disease, discuss sex differences with immune signaling pathways, and sex differences with viral infections and vaccine responses with the ultimate goal to leverage these insights for the development of sex-specific therapeutic interventions for immune-related diseases.
    Keywords:  Xist RNA; X‐chromosome inactivation; autoimmunity; immune signaling; sex differences; viral infections
    DOI:  https://doi.org/10.1111/imr.70107
  2. Immunol Rev. 2026 Mar;338(1): e70101
    Sex Differences in the Impact of Obesity on Immunity.
    Saranya Vijayakumar, Saurav Pantha, Shristy Budha Magar, Santosh Dhakal.
      The prevalence of obesity has increased significantly worldwide in the past few decades and is anticipated to rise further in the future. Obesity, characterized by excessive fat accumulation and chronic low-grade inflammation, dysregulates innate and adaptive immune responses, thereby increasing the risk of infectious diseases, cardiovascular diseases, and cancers. Males and females differ considerably in patterns of fat distribution, adipose tissue inflammation, and adipocytokine production, resulting in substantial sex-specific differences in metabolic health outcomes during obesity. Despite growing evidence of its importance, biological sex remains underprioritized in preclinical, clinical, and epidemiological obesity-related research. In this review, we explore the impact of biological sex on obesity-associated immune dysregulation and its consequences for a range of health outcomes, including infectious diseases, vaccine-induced immunity, autoimmune diseases, cancer, and cardiometabolic risk. We highlight recent findings from animal models and human studies to discuss the mechanistic roles of sex steroids and chromosome complements in shaping fat distribution, adipose inflammation, gut microbiota composition, and systemic inflammation, which collectively drive sex differences in obesity-associated immune responses. Greater consideration of biological sex in obesity research is essential to better understand disease risk, develop targeted interventions, and improve care.
    Keywords:  M1 macrophage; X‐chromosome inactivation; androgen; estrogen; leptin; metabolic disease; regulatory T cells
    DOI:  https://doi.org/10.1111/imr.70101
  3. Naunyn Schmiedebergs Arch Pharmacol. 2026 Jan 23.
    Sex matters: mechanistic insights into sex-driven patterns of autoimmunity and implications for pharmacotherapy.
    Mariana Soares Guedes, Daniela Yildiz.
      Autoimmune diseases (AiDs) affect up to 10% of the global population and exhibit striking differences between sexes. These disparities encompass prevalence, incidence, age at onset, disease severity and how patients respond to treatment. This review provides a comprehensive overview of the key biological mechanisms underlying sex-biased autoimmunity across multiple levels, including the immunomodulatory roles of sex hormones, sex-specific innate and adaptive immune responses, X-chromosome gene dosage and escape from inactivation as well as epigenetic regulation of immune pathways. In addition, we address how environmental and lifestyle factors, such as smoking, infections and the gut microbiome interact with sex-specific biology to shape autoimmune risk. Finally, we consider the pharmacological implications of sex differences, including variability in drug efficacy, safety and immune-related adverse events, further highlighting current gaps in sex-stratified clinical research. Recognizing sex as a fundamental biological variable is essential for advancing the understanding of AiDs and for the development of more effective, tailored therapeutic strategies.
    Keywords:  autoimmune; pathomechanisms; pharmacotherapy; sex-bias
    DOI:  https://doi.org/10.1007/s00210-026-04990-x
  4. bioRxiv. 2025 Dec 05. pii: 2025.12.02.691857. [Epub ahead of print]
    Ovarian Hormones and Obesity Drive Th17-mediated Airway Inflammation through Estrogen Receptor Signaling.
    Emely Henriquez-Pilier, Jacqueline-Yvonne Cephus, Shelby Kuehnle, Elie Tannous, Alessandra Tomasello, Kaitlin McKernan, R Stokes Peebles, Katherine N Cahill, Jeffrey C Rathmell, Dawn C Newcomb.
      Obesity is a risk factor for increased prevalence and severity of asthma, particularly in females. As adults, females have increased prevalence of asthma compared to males. Yet, the mechanisms remain unclear on how sex hormones and obesity increase airway inflammation. We hypothesize that estrogen signaling through estrogen receptor-alpha (ER-α) in T cells increased airway inflammation in the context of obesity. To test our hypothesis, we utilized a high fat (HFD) on female and male mice that underwent ovariectomy or gonadectomy or in Esr1 fl/fl X Cd4 Cre+ male and female mice. As controls, mice in similar groups were fed normal chow. After 8-12 weeks on diets, house dust mite (HDM) sensitization and challenge occurred in all mice. Lungs and BAL fluid were harvested 24 hours after the last challenge. Ovarian hormones and ER-α signaling in T cells increased eosinophils, neutrophils, and Th17-mediated airway inflammation in the lungs of obese female mice. Additionally, using PBMCs from a well-characterized obese asthma cohort, we determined that obese women with asthma had increased Th17 cells compared to obese men with asthma. Our results show that ER-α signaling in T cells increases Th17-mediated airway inflammation in obese mice and that Th17 cells circulate at higher frequencies in women with asthma compared to men with asthma. Further research into the interplay between hormonal signaling and immune responses in asthma is essential for developing personalized treatments.
    One Sentence Summary: Estrogen receptor-alpha signaling, in the context of obesity, increases allergen-induced Th17-mediated airway inflammation in female mice.
    DOI:  https://doi.org/10.64898/2025.12.02.691857
  5. Endocrine. 2026 Jan 21. 91(1): 41
    Hormonal and metabolic profiles in teenagers and young adults with polycystic ovary syndrome (PCOS).
    Anna Bareja, Adrianna Adamczyk, Agata Seman, Olga Kacalska-Janssen, Robert Jach, Magdalena Piróg.
      
    Keywords:  Body mass index; Free androgen index; Insulin resistance; Polycystic ovary syndrome
    DOI:  https://doi.org/10.1007/s12020-025-04487-2
  6. JHEP Rep. 2026 Feb;8(2): 101678
    Inhibition of estrogen receptor alpha stabilizes regulatory T cell function in autoimmune hepatitis.
    Lina Zhang, Barbora Gromova, Du Hanh Nguyen, Cortney Cagle, Graziela S Gomes, William Li, Li Gao, Wei Zhang, Jonathon J Graham, Na Wang, Ahmadreza Kalbasi, Eva Csizmadia, Angelina Wei, Jessica Cassavaugh, Alan Bonder, Vilas Patwardhan, Sizun Jiang, Satya K Kota, Maria Serena Longhi.
       Background & Aims: Regulatory T cell (Treg) dysfunction is a hallmark of autoimmune hepatitis (AIH), a serious hepatopathy often progressing to end-stage liver disease despite immunosuppression. Treg impairment in AIH has been linked to defective signaling through the aryl hydrocarbon receptor (AhR), a modulator of adaptive immunity. Herein, we investigated whether increased estrogen receptor alpha (ERα), an AhR non-canonical binding partner, impacts Treg immunity and contributes to the sex bias observed in AIH.
    Methods: Tregs were isolated from the peripheral blood of pre-menopausal, post-menopausal and male patients with AIH, as well as controls. Their function, stability, transcriptome and response to AhR were assessed in the absence or presence of methylpiperidinopyrazole (MPP), an ERα-selective antagonist. Therapeutic effects of MPP were tested in a model of Concanavalin-A-induced liver injury in humanized mice.
    Results: ERα was upregulated in Tregs from pre-menopausal females with AIH (1.1 ± 0.3) compared with healthy pre-menopausal females (0.4 ± 0.1; p = 0.038), and in pre-menopausal compared with post-menopausal females with AIH (0.3 ± 0.1; p = 0.04). In pre-menopausal females with AIH, MPP enhanced Treg suppressive capacity (2.5-fold increase; p = 0.001), restored response to AhR activation (2-fold increase; p = 0.03), and reduced functional plasticity, evidenced by decreased IL-17A and RORC expression under pro-inflammatory conditions. MPP also ameliorated Concanavalin-A-induced hepatitis in NOD/scid/gamma mice reconstituted with human CD4+ ERα+ cells, as shown by reduced ALT levels (101 ± 24 vs. 25 ± 8; p = 0.024), diminished hepatic inflammation on histology, and increased intrahepatic CD4+FOXP3+ and CD4+CD39+ T-cell frequencies. Bioinformatic and inhibition analyses identified hypoxia-inducible factor-1α as a key inducer of ERα in AIH Tregs.
    Conclusions: ERα upregulation drives Treg dysfunction in pre-menopausal females with AIH and likely contributes to the sex bias in the disease. ERα blockade stabilizes Tregs and limits inflammation in vivo, representing a promising therapeutic strategy to enhance and sustain immune tolerance in AIH.
    Impact and implications: Regulatory T cell (Treg) dysfunction plays a key role in the breakdown of immune tolerance in autoimmune hepatitis (AIH), a severe hepatopathy that often progresses to end-stage liver disease despite immunosuppression. Here we report that upregulation of estrogen receptor-alpha (ERα) alters Treg function and stability in pre-menopausal females with AIH, and that blockade of ERα using a specific antagonist stabilizes Tregs and curbs inflammation in humanized mice with liver injury. These findings implicate aberrant ERα signaling in the sex bias of AIH and support ERα inhibition as a potential therapeutic strategy to re-establish immune tolerance.
    Keywords:  autoimmune hepatitis; estrogen receptor-alpha; hypoxia-inducible factor 1-alpha; regulatory T cells
    DOI:  https://doi.org/10.1016/j.jhepr.2025.101678
  7. Toxicol Ind Health. 2026 Jan 18. 7482337261417731
    Reproductive toxicity of endosulfan: Mechanisms and impacts on female and male reproductive health.
    Elizabeth Glanet Durom, V A Aneesha, T S Shyamkumar, Ajmi Bin Azeez, C S Celus, Ayushi Vaidhya, Subhashree Parida, Madhu C Lingaraju, Thakur Uttam Singh, Dinesh Kumar.
      Endosulfan is a broad-spectrum organochlorine pesticide widely used in many developing countries despite its high toxicity potential. Endosulfan, listed as potent endocrine-disrupting chemical and xenoestrogen, gains importance for its potential to cause reproductive and developmental dysfunction. In females, endosulfan disrupts ovarian and uterine development, leading to infertility, miscarriage, and developmental toxicity. It acts by mimicking estrogen and interferes with estrogen and androgen pathways, impacting hormone regulation and gene expression, including estrogen receptor α (ERα) and progesterone receptors. Endosulfan triggers oxidative stress in ovaries, reduces follicle count, and impairs uterine differentiation, affecting embryo implantation. Additionally, it alters gene expression and causes epigenetic modifications, contributing to reproductive dysfunctions. In males, endosulfan affects spermatogenesis by causing oxidative stress, mitochondrial dysfunction, and lipid peroxidation. It reduces sperm quality, motility, and quantity, with effects on testicular tissues, sperm chromatin condensation, and enzymatic activity. Oxidative damage, increased reactive oxygen species (ROS), and disrupted energy metabolism are central to its toxicity. Epidemiological studies also link pesticide exposure to reduced sperm counts, higher DNA fragmentation, and infertility. Moreover, endosulfan can cross the placental barrier, leading to fetal resorption, malformations, and maternal toxicity. This review provides a comprehensive overview of the reproductive toxicity of endosulfan in males and females. We also highlight the various possible mechanisms of reproductive toxicity of endosulfan and its potential to impart deleterious effects over HPG axis, gonads, and uterine differentiation and development and implantation.
    Keywords:  endocrine disruption; endosulfan; female; male; reproductive toxicity
    DOI:  https://doi.org/10.1177/07482337261417731
  8. Front Endocrinol (Lausanne). 2025 ;16 1694559
    Sex-specific effects of peptidyl arginine deiminase 4 deficiency in the cafeteria diet-induced obesity-associated metabolic complications.
    Andrej Feješ, Emil Bečka, Ivana Feješ Slivková, Kristína Macáková, Emőke Šteňová, Michal Pastorek, Peter Celec, Roman Gardlík, Katarína Šebeková, Veronika Borbélyová.
       Background: Obesity is a global health challenge linked to chronic non-communicable diseases. Low-grade inflammation and altered immune responses, including neutrophil extracellular trap (NET) formation, contribute to metabolic complications. Peptidyl arginine deiminase 4 (PAD4) is critical for NET formation, and its inhibition shows therapeutic potential. However, the sex-specific effects of PAD4 deficiency in diet-induced obesity remain unexplored.
    Methods: This study investigated the impact of PAD4 deficiency on obesity-related metabolic pathologies in male and female C57BL/6 wild-type (WT) and Pad4(-/-) mice (n=5-6/group) fed a 22-week obesogenic cafeteria (CAF) diet. We hypothesized that PAD4 deficiency would ameliorate obesity-related metabolic and behavioral complications for both sexes. Body weight and composition, glucose and lipid metabolism, liver damage markers, and behavior were assessed. NETs were quantified via flow cytometry.
    Results: Pad4(-/-) males on CAF diet exhibited delayed obesity onset, lower body weight gain, and improved dyslipidemia than WT CAF males. This was associated with enhanced metabolic adaptation, indicated by higher brown adipose tissue temperature in Pad4(-/-) males. Conversely, Pad4(-/-) females on the CAF diet showed comparable weight gain to WT CAF females, similar or worsened dyslipidemia, impaired glucose metabolism, and higher liver lipid accumulation. While WT CAF females showed increased brown adipose tissue temperature, Pad4(-/-) CAF females did not.
    Conclusion: PAD4 deficiency exerts sex-specific effects on obesity-related metabolic complications in mice. Inhibition of NET formation appears protective in males but not females on an obesogenic diet. These findings underscore the importance of considering sex as a biological variable in obesity research and developing sex-specific therapies.
    Keywords:  gender; insulin resistance; metabolic syndrome; neutrophil extracellular traps; steatohepatitis; thermogenesis
    DOI:  https://doi.org/10.3389/fendo.2025.1694559
  9. bioRxiv. 2025 Dec 05. pii: 2025.12.03.690226. [Epub ahead of print]
    Androgen receptor contributes to radioresistance through DNA repair and autophagy in AR-positive prostate cancer cells.
    Ken-Ichi Kudo, Qianhua Feng, Maria Isabel Chosco, Jonathan M Anzules, Ziyi Huang, Kavya Achanta, Leslie Wenning, Jeshwanth Mohan, June-Wha Rhee, Maedeh Mohebnasab, Evita Sadimin, Zhao V Wang, Yun Rose Li.
      Androgen receptor (AR) is a critical therapeutic target in prostate cancer (PCa), and androgen blockade is known to act synergistically with radiation therapy. However, the mechanisms through which AR modulates radiation response are not yet fully understood. In this study, we aimed to investigate the role of AR in mediating radioresistance in PCa. AR-positive LNCaP and castration-resistant C4-2 cells exhibited significantly higher radioresistance than AR-negative cells, as determined by apoptosis and cell viability assays. Following irradiation, most LNCaP cells were arrested in the G1 phase, accompanied by rapid p53 activation and p21 induction. Consistently, AR silencing significantly increased radiosensitivity and reduced DNA-PKcs expression and phosphorylation, suggesting that AR enhances DNA repair, likely through non-homologous end joining (NHEJ). At the cellular level, irradiation markedly induced macroautophagy in LNCaP and C4-2 cells, as evidenced by increased LC3B-II accumulation and autophagic vacuole formation, and the upregulation of 11 autophagy-related genes was identified by whole-transcriptomic analysis. To assess their functional relevance, we performed siRNA-mediated knockdown of selected autophagy-related genes and assessed cell viability and Annexin V/PI staining. Notably, BECN1 and LC3 knockdown significantly enhanced radiosensitivity, with BECN1 knockdown showing an effect comparable to that observed with AR silencing. These results suggest that radiation-induced autophagy promotes the survival of AR-positive prostate cancer cells. Moreover, immunohistochemical analysis of ex vivo- irradiated, patient - derived PCa tissues from patients with newly diagnosed high - Gleason score prostate cancer undergoing prostatectomy further demonstrated that radiation-induced autophagy supports the survival of high-grade AR-positive tumor cells. Collectively, our findings reveal that AR promotes radioresistance in PCa by enhancing both DNA repair and autophagy.
    DOI:  https://doi.org/10.64898/2025.12.03.690226
  10. Sex Dev. 2026 Jan 22. 1-20
    Genetic, endocrine and epigenetic mechanisms underlying sexual size dimorphism in fish.
    Silvia Beato, Gabriel Ecker-Eckhofen, Changwei Shao, Francesc Piferrer.
      Background Sexual size dimorphism (SSD), i.e., size difference between sexes, is common in fishes and spans from negligible to extreme body size differences, with both female‑ and male‑biased directions. While evolutionary drivers behind SSD such as sexual selection, fecundity selection and natural selection are increasingly well understood, our understanding of the underlying mechanisms of how sex‑specific growth trajectories develop is less clear. Summary Here we review recent findings of such mechanisms in fishes and reveal that SSD arises from an interplay of sex-linked and autosomal genetic factors. In teleosts, master sex-determining genes and growth regulators such as dmrt1/dmY, sdY, amhr2by, gdf6Y and gsdfY play key roles, while quantitative trait loci (QTL) influence growth and maturation, further contributing to SSD. Essential sex-specific regulation of hormones across brain, pituitary, liver and gonad determines SSD directionality. Epigenetic mechanisms, such as DNA methylation and non-coding RNA further modulate gene expression in growth and reproductive pathways. We identify the basic mechanisms, highlight knowledge gaps, and propose that multi-omics approaches can disentangle sex effects from dimorphism-specific regulation, linking together endocrine, genetic and epigenetic drivers. Key Messages 1. At the mechanistic level, SSD results from an interplay of genetic, endocrine and environmental influences. 2. Sex chromosomes and autosomal loci form the genetic architecture that shapes growth differences between males and females. 3. The somatotropic axis, involving GH/IGF signaling, together with the actions of sex steroids, serves as a central effector system underlying SSD in fish. 4. Epigenetic mechanisms help establish and maintain sex-specific gene expression programs, but integrative multi‑omic approaches are needed to uncover causal relationships and phenotypic plasticity in SSD.
    DOI:  https://doi.org/10.1159/000550574
  11. Biomed Pharmacother. 2026 Jan 19. pii: S0753-3322(26)00046-6. [Epub ahead of print]195 119014
    Integrated transcriptomic and proteomic profiling identifies an interferon-dependent inflammatory endotype in sepsis.
    Andrian Fratea, Anca-Lelia Riza, Florentina Dumitrescu, Stefania Dorobantu, Andrei Pirvu, Adina Dragos, Andra Grigorescu, Ioana Streata, Mihai G Netea, Vinod Kumar, Collins K Boahen.
       BACKGROUND: Sepsis is a major cause of mortality worldwide, with modest improvements in the last decades. A significant challenge for the outcome improvement lies in the marked disease heterogeneity among patients. Stratifying patients into distinct endotypes is needed for more precise interventions. This study investigates the transcriptomic landscape of sepsis patients stratified by their inflammatory endotype.
    METHODS: We obtained peripheral blood mononuclear cells from 125 sepsis patients (as per Sepsis-2 criteria) and 299 volunteers as part of the Functional Genomics in Severe Infections project (FUSE). RNA sequencing was conducted to identify differentially expressed genes and enriched pathways. We compared the transcriptomic profiles of previously defined "high-" and "low-inflammatory" endotypes, obtained through targeted inflammatory proteomics.
    RESULTS: Sepsis was linked to widespread transcriptional changes in innate immunity genes, notably those linked to phagocytosis and antimicrobial peptides, alongside paradoxical reduced NK cell-mediated immunity. Adaptive immunity genes, particularly those involved in T cell differentiation, were downregulated. Importantly, infection etiology and infection site had no discernible impact on gene expression profiles. In the "high-inflammatory" endotype, interferon-associated chemokines CXCL9 and CXCL10 were markedly upregulated at the transcription level in peripheral blood mononuclear cells, with concordant elevations in their circulating serum concentrations, as assessed by targeted proteomics and ELISA.
    CONCLUSION: Immune dysregulation in sepsis is more driven by disease severity than infection site. The robust activation of the interferon-gamma-CXCL9-CXCL10 axis observed in the "high-inflammatory" endotype may present a promising target for personalized immunotherapies.
    Keywords:  Endotype; Innate immunity; Interferon; Omics; Proteomics; Sepsis; Transcriptomics
    DOI:  https://doi.org/10.1016/j.biopha.2026.119014
  12. Med Sci (Basel). 2026 Jan 11. pii: 38. [Epub ahead of print]14(1):
    Beyond XX and XY, Understanding Sex Differences in Leukemia.
    Mai Mostafa, Alaa Elhaddad, Mohamed Z Gad, Rasha Hanafi, Hanaa Rashad, Sami El Deeb.
      The major subtypes of leukemia show sex differences. This review summarizes current knowledge and identifies gaps regarding sex differences across acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, and chronic lymphoblastic leukemia in epidemiology, mortality and survival rates, risk factors, and epigenetic, metabolomic, and sex-specific patterns. Males have higher incidence and mortality rates of leukemia compared to females, emphasizing the importance of biological sex. Underreporting of sex differences in leukemia is highlighted, suggesting that sex is often overlooked as a research variable. A significant clinical observation is that women demonstrate higher overall survival rates but experience more severe treatment-related toxicity. Clinically, women tend to survive longer but experience more severe side effects. In contrast, a significant clinical observation in pediatric leukemia contradicts this enigma, suggesting that sex differences may be less pronounced during childhood. These differences play a significant role in how the disease develops. This review presents a sex-based perspective for hematological and biochemical patterns, genetic risk factors, environmental, lifestyle, and parental risk factors, epigenetics and metabolites. Furthermore, males and females might have different responses to the same toxic, environmental, and hormonal exposures. Trying to understand these disparities better based on molecular mechanisms is considered an approach for precision medicine.
    Keywords:  enigma; epidemiology; epigenetics; leukemia; metabolites; risk factors; sex differences; sex-based
    DOI:  https://doi.org/10.3390/medsci14010038
  13. Biochim Biophys Acta Mol Basis Dis. 2026 Jan 19. pii: S0925-4439(26)00016-5. [Epub ahead of print] 168168
    Placental aberrant inflammation and spatial-specific lipid metabolism contribute to hypertensive disorder of pregnancy susceptibility in preeclampsia offspring.
    Pei-Ran Hu, Jing-Hui Xu, Yan Shi, Ying Zhu, Gao-Chen Zhang, Jie-Ru Yang, Yue Xu, Ming-Hao Li, Xian-Hua Lin, Yu Zhang, He-Feng Huang.
      Epidemiological studies have demonstrated that daughters of preeclamptic mothers have an increased risk of hypertensive disorders of pregnancy (HDP), but the underlying mechanisms remain unclear. To investigate the molecular changes underlying this HDP intergenerational transmission, we established an L-NAME-induced PE model in pregnant mice (F0) and examined female offspring (F1) during their pregnancies. F1 females developed gestational hypertension in late pregnancy, accompanied by enlarged placental labyrinthine areas and elevated VGFR1 expression, despite normal circulating sFlt1 levels. Across gestation, F2 placentas exhibited sustained impairment of apolipoprotein-mediated lipid transport beginning at mid-gestation, while inflammatory and HIF1α pathways were mainly activated at late gestation. Spatial transcriptomic data further showed that apolipoproteins were predominantly localized to yolk sac regions, whereas inflammatory factors exhibited widespread distribution. Importantly, F1 maternal lipid profiles remained normal before conception but manifested elevated serum triglyceride levels during pregnancy, concurrent with placental lipid accumulation. This pregnancy-specific dyslipidemia suggests that placental lipid metabolism dysfunction may contribute to maternal lipid dysregulation. Clinical validation in 28,117 women further confirmed that elevated mid-gestation triglyceride levels were strongly associated with HDP risk, consistent with the dyslipidemia observed in our mouse model. Together, these findings demonstrate that pregnancy-specific lipid dysregulation represents a conserved mechanism linking placental dysfunction to HDP susceptibility. Our study provides mechanistic insights into the intergenerational transmission of PE and identifies mid-gestation maternal lipid profiles as potential predictive biomarkers, offering a basis for early risk assessment and future therapeutic targeting.
    Keywords:  Hypertensive disorder of pregnancy; Intergenerational transmission; Lipid metabolism; Placental dysfunction; Preeclampsia
    DOI:  https://doi.org/10.1016/j.bbadis.2026.168168
  14. Aging Cell. 2026 Feb;25(2): e70387
    Blood Cell Mitochondrial Respiration Increases With Age and Varies by Sex in Healthy Adults.
    Howard J Phang, Jaclyn Bergstrom, Benjamin Keri, Stephanie R Heimler, Stephen Dozier, Lina M Scandalis, David Wing, Daniel Moreno, Nina N Sun, Anthony J A Molina.
      Mitochondrial dysfunction is recognized as a biological hallmark of aging; however, bioenergetic capacity across the healthy human life course remains insufficiently characterized. While aging is generally associated with a systemic decline in mitochondrial function ("age-related bioenergetic decline"), recent research suggests that age-related bioenergetic differences are context dependent. Blood cells are extensively utilized as accessible samples for human bioenergetic profiling; therefore, our goal was to characterize bioenergetic capacity in platelets, peripheral blood mononuclear cells (PBMCs), monocytes, and lymphocytes of healthy adults from the San Diego Nathan Shock Center Clinical Cohort representative of the adult life course (20-80+ years of age). In our sample of 72 adults, we found that chronological age was positively associated with PBMC (maximal respiration [Max] β = 0.147, p = 0.028) and lymphocyte respiratory capacity (Max β = 0.135, p = 0.041). Notably, the pattern of age-related differences varied by sex; age showed a weak positive association with platelet respiration (Max β = 0.219, p = 0.037) in men but not in women. Similarly, age showed a strong positive association with PBMC respiration (Max β = 0.206, p = 0.018) in women but not in men. We also explored the relationship between glycolysis and respiration and found strong positive associations in platelets, PBMCs, and monocytes, but not lymphocytes. It is possible that, despite our cohort consisting of healthy, disease-free individuals, the elevated respiratory capacity in older adults may be reflective of compensatory mechanisms that require further investigation. Nonetheless, these findings underscore the importance of considering biological context, such as donor health, sex, and tissue type, in understanding age-related bioenergetic differences.
    DOI:  https://doi.org/10.1111/acel.70387
  15. Elife. 2026 Jan 21. pii: e105835. [Epub ahead of print]15
    Western lifestyle linked to maladaptive trained immunity.
    Aurelia Josephine Merbecks, Christabel Mennicken, Dennis Marinus de Graaf, Kateryna Shkarina, Theresa Wagner, Eicke Latz.
      Trained immunity (TI) refers to a state of innate immune cells that, after encountering an initial stimulus and undergoing epigenetic reprogramming and metabolic changes, allows them to respond more effectively to a subsequent challenge. TI yields a survival advantage, particularly in a pathogen-rich context. However, maladaptive TI may damage the host by exacerbating inflammatory diseases. Here we review which aspects of Western lifestyle may contribute to maladaptive TI, including a Western diet, periodontitis, chronic psychological stress, and environmental triggers such as air pollution and microplastics. Finally, we consider lifestyle intervention as a way to prevent or reduce the impact of maladaptive TI.
    Keywords:  Western diet; autoinflammation; immunology; infectious disease; inflammation; interleukin-1; maladaptive; trained immunity
    DOI:  https://doi.org/10.7554/eLife.105835
  16. Anim Reprod Sci. 2026 Jan 12. pii: S0378-4320(26)00008-4. [Epub ahead of print]287 108105
    Dihydrotestosterone binding to the androgen receptor inhibits apoptosis in ovine undifferentiated granulosa cells via AMH signaling.
    Yufen Zhao, Haijiang Liu, Zhe Mu, Haijun Li.
      Although dihydrotestosterone (DHT), androgen receptor (AR), and anti-Müllerian hormone (AMH) play key roles in ovarian function, their precise contributions and synergistic roles in mammalian follicular development remain unclear. In this study, we first evaluated whether ovine granulosa cells (GCs) undergo differentiation during vitro culture and then determined methods for inhibiting differentiation. Following the culture of GCs with DHT (10-7 mol/L) and the AR antagonist enzalutamide (ENZ) (10-6 mol/L) separately or in combination for 48 h, an apoptosis assay revealed that the interaction between DHT and AR decreases sheep GC apoptosis. DHT significantly increased the AMH concentration through AR signaling. In addition, DHT and AR significantly increased the intracellular AMH level, and the use of rAMH (70 pg/mL), a sheep recombinant AMH, significantly upregulated the expression of the BCL2 mRNA in GCs. In summary, GCs undergo spontaneous differentiation during in vitro culture, and the use of the specific luteinizing hormone receptor (LHR) antagonist BAY-899 to inhibit their differentiation establishes an in vitro culture model that maintains GC characteristics. Thus, the interaction between DHT and AR may be involved in the accumulation of AMH signals, affecting GC apoptosis. We provide new mechanistic insights into the roles of DHT and AR in attenuating sheep GC apoptosis. The finding that potential cross-points between DHT/AR-induced intracellular signals affect GC apoptosis will help elucidate the mechanisms regulating early follicular development.
    Keywords:  Anti-Müllerian hormone; Apoptosis; Dihydrotestosterone; Granulosa cell; Nondifferentiation; Sheep
    DOI:  https://doi.org/10.1016/j.anireprosci.2026.108105
  17. Asian J Androl. 2026 Jan 20.
    Clinical features and genetic analysis of androgen receptor gene variants in 30 prepubertal patients with androgen insensitivity syndrome.
    Jia-Nan Li, Jiang Wei, Jing Hui, Zi-Xuan Wang, Ji-Yun Yang.
      Androgen insensitivity syndrome (AIS; Online Mendelian Inheritance in Man [OMIM; #300068]) is an X-linked recessive disorder caused by pathogenic variants in the androgen receptor (AR) gene located in the Xq11-q13 region. In this retrospective study of 30 patients with AIS, next-generation sequencing identified 24 variants in AR, including 20 missense, 1 nonsense, and 3 splice-site variants. Seven novel variants were detected in 8 patients. Of the 24 variants, 15 were classified as likely pathogenic, 8 as pathogenic, and 1 as of uncertain significance. Variants included 5 de novo and 24 familial cases. These AR variants were predominantly located in the functional domains, with the ligand-binding domain (LBD) harboring 10 variants, the DNA-binding domain (DBD) harboring 5 variants, the N-terminal domain (NTD) harboring 2 variants, and the hinge region (HR) harboring 1 variant. The highest variant detection rate occurred in exon 5 (11/30), followed by exon 3 (9/30). These findings advance our understanding of genotype including 20 missense, 1 nonsense, and 3 splice-site variants through the identification of 7 novel variants.
    Keywords:  ; 46,XY DSD; AIS; disorder of sex development
    DOI:  https://doi.org/10.4103/aja202578
  18. Nat Commun. 2026 Jan 20. 17(1): 717
    NCOA1 is a gatekeeper of the sexually dimorphic thermogenic activity of white adipose tissue.
    Mounia Tannour-Louet, Didier F Pisani, Hichem Bouguerra, Alycia Zedda, Marine Bourcier, Noura Lamghari, Nadine Gautier, Benoit Chaput, Elodie Riant, Anne Bouloumié, Emilie Montastier, Nathalie Viguerie, Dominique Langin, Ez-Zoubir Amri, Pierre Gourdy, Jean-François Tanti, Mireille Cormont, Jean-François Louet.
      Premenopausal women preferentially store fat in subcutaneous depots, which provides protection against cardiometabolic disease. Their white adipose tissue also exhibits a more thermogenic, brown-like profile compared with that of men, yet the mechanisms underlying this sex-specific benefit remain unclear. Here, we show that Nuclear Receptor Coactivator 1 is highly expressed in human subcutaneous fat, with further induction during the conversion of white to beige adipocytes and in response to caloric restriction. Loss of Nuclear Receptor Coactivator 1 in subcutaneous adipocytes revealed a cell-autonomous role in promoting beiging by directly regulating the thermogenic factor Uncoupling Protein 1 and sex-dependent mitochondrial gene networks activated by cold and adrenergic stimulation. Acting together with GATA binding protein 3, it establishes elevated basal thermogenic tone in female subcutaneous fat. Female mice lacking this coregulator progressively developed obesity and glucose intolerance, and a male-like fat distribution, with increased visceral fat and reduced beige adipocytes. These findings identify Nuclear Receptor Coactivator 1 as a sex-specific determinant of adipose tissue remodelling and female metabolic resilience.
    DOI:  https://doi.org/10.1038/s41467-025-65229-6
  19. Horm Behav. 2026 Jan 17. pii: S0018-506X(26)00011-5. [Epub ahead of print]178 105886
    Growing up in comfort: Environmental enrichment shapes maternal approach and sex differences in offspring neuroendocrine profiles in laboratory mice.
    Lucas F Fowler, Alexandre Maekawa, T Nadine Burry, Jessica Vaters, Stephanie Salia, Meagan E Hinks, Kerri M Sparkes, Ashlyn Swift-Gallant.
      The physical environment modulates the maternal brain and affects maternal-offspring dynamics, with downstream effects on neonatal development. In this study, we examined whether environmental enrichment (EE) influences maternal approach, neonatal ultrasonic vocalizations (USVs), and early neuroendocrine development in mice, focusing on hormonal pathways associated with maternity, stress responsivity, and gonadal hormones. Nulliparous female C57BL/6 mice were housed in EE or standard (ST) conditions prior to mating. EE cages were larger and contained extra bedding and enrichment items. Litters were culled to four pups (2/sex), and maternal approach and pup USVs were recorded on postnatal days (PND) 6 and 8 using a modified three-chamber protocol. EE dams made fewer entries into female interaction zones than ST counterparts. EE also increased USV call numbers and decreased call frequencies among pups. These effects were not sex-dependent, and despite higher emission rates, USV parameters did not correlate with maternal response in the EE group. Gene expression analyses revealed that EE altered stress- and care-related genes in the maternal brain, downregulating Prlr (prolactin receptor) and Nr3c2 (mineralocorticoid receptor) in the cortex and upregulating Prlr while downregulating Nr3c2 and Oxtr (oxytocin receptor) in the diencephalon. Further, EE housing changed neuroendocrine profiles in male pups, but not females, suggesting benefits to neurodevelopment (increased brain-derived neurotrophic factor) and alterations to sexual differentiation (Ar [androgen receptor] and Esr1 [estrogen receptor alpha]) and stress reactivity (Nr3c1 [glucocorticoid receptor] and Nr3c2). These findings highlight how environmental context can shape maternal brain and behaviour and imprint on offspring neuroendocrine development in a sex-dependent manner.
    Keywords:  Development; Environmental enrichment; Laboratory mice; Maternal-offspring dynamics; Sex differences; Ultrasonic vocalizations
    DOI:  https://doi.org/10.1016/j.yhbeh.2026.105886
  20. Front Immunol. 2025 ;16 1707736
    Gut microbiome composition influences immunologic alterations in the blood and gut of HIV-positive and HIV-negative men who have sex with men.
    Charles Preston Neff, Janet Siebert, Mallory Karr, Ricky Lippincott, Rachel Kvaal, Amy T Noe, Elena Wall, Nichole Nusbacher, Suzanne Fiorillo, Blair P Fennimore, Thomas B Campbell, Catherine Lozupone, Brent E Palmer.
       Background: HIV infection and factors associated with sexual activity among men who have sex with men (MSM) can dysregulate relationships between the gut microbiome and immune system.
    Methods: To explore these relationships in depth, blood and colonic biopsy samples from HIV+ and HIV- MSM and non-MSM were analyzed using Cytometry by Time of Flight (CyTOF). Immune profiles were then integrated with gut microbiome composition and MSM-related behaviors.
    Results: HIV infection status influenced immune cell composition in colonic biopsies, marked by a loss of CD4⁺ CD103⁺ and CD8⁺CD103⁺ tissue-resident T cells and group 3 innate lymphoid cells (ILC3s). In the blood, HIV status was linked to reductions in circulating group 2 innate lymphoid cells (ILC2s), and naïve CD8⁺ T cells, while mucosal-associated invariant T (MAIT) cells were reduced in MSM engaging in high-risk sexual behaviors regardless of HIV status. Network analysis revealed distinct, tissue-specific relationships between immune cell populations and gut microbial taxa, further shaped by both HIV infection and MSM-associated factors.
    Conclusions: These findings provide new insights into host:microbe interactions, with implications for immune regulation, HIV persistence, and transmission among MSM.
    Keywords:  CyTOF; HIV; antiretroviral therapy; colonic; inflammation; men who have sex with men; microbiome; sexual behavior
    DOI:  https://doi.org/10.3389/fimmu.2025.1707736
  21. Klin Onkol. 2025 ;38(6): 436-446
    Why sex and gender matter in cancer research and care.
    J Staňková, M Hajdúch.
       BACKGROUND: Biological sex and gender significantly influence cancer incidence, biology, disease progression, treatment response, and long-term survival. These differences arise from a complex interplay of hormonal, genetic, epigenetic, immunological, and behavioral factors. Notable disparities have been observed in colorectal, lung, and bladder cancers - including histological subtypes, immune responses, and treatment outcomes. Women are more susceptible to chemotherapy toxicity, often face delayed diagnosis, and experience higher psychosocial burden. In contrast, men tend to show higher cancer-related morbidity and mortality. Transgender and non-binary individuals remain largely underrepresented in cancer research. Furthermore, preclinical models frequently overlook the sex of animal or cellular samples, limiting translational relevance. Emerging technologies - such as multi-omics approaches, 3D human organoids, and artificial intelligence - provide promising tools to better understand sex-specific mechanisms in cancer development and treatment, and will enable future personalization of oncological care according to the patient's sex.
    PURPOSE: This review aims to summarize current knowledge on the influence of biological sex and gender on cancer incidence, tumor biology, and therapeutic response, with additional focus on behavioral and psychosocial factors. Special attention is given to colorectal, lung, and bladder cancers as model malignancies with sex-specific differences, and to the ongoing challenges in preclinical research and clinical practice.
    CONCLUSION: Sex and gender are key determinants of oncological outcomes and should be systematically incorporated into research design, clinical trial methodology, personalized therapy, and health policy. Their integration is not only a scientific imperative but also an ethical necessity on the path toward precise and equitable cancer care.
    Keywords:  Gender identity; gender ; neoplasms; precision medicine; research; sex; tumors
    DOI:  https://doi.org/10.48095/ccko2025436
  22. Front Immunol. 2025 ;16 1695213
    Exploring the impact of age, sex and life experiences on plasma inflammatory profiles through comparative proteomics.
    Martina Bartolucci, Olga Utyro, Anita Muraglia, Alessia Repetto, Vanessa Agostini, Monica Pizzonia, Silvia Ottaviani, Gino Tripodi, Gilberto Filaci, Ranieri Cancedda, Andrea Petretto, Maddalena Mastrogiacomo.
       Background: In the heterochronic parabiosis model it has been shown that blood from elderly animals exhibits markedly reduced rejuvenating effects compared to that of young organisms. Furthermore, human plasma from older subjects, when used as a supplement in cell culture media, is significantly less effective than plasma derived from younger individuals. This study analyzed plasma from a cohort of 229 subjects by a proteomic approach to reveal age-related changes.
    Methods: A mass spectrometry-based proteomic analysis was performed on plasma samples from 3 age-groups: a prepubertal, a healthy young adult group and a cohort of individuals over 75 years old with three different life-experiences. An additional parallel study was conducted by a Milliplex Luminex assay.
    Results: The proteomic analysis revealed a chronic inflammatory state in the elderly population, along with complement activation and impaired regulation of blood coagulation. This inflammatory condition was confirmed by Luminex assay, showing elevated levels of classical pro-inflammatory cytokines in the plasma of elderly individuals. Moreover, the elderly group showed a reduced production of antibody light chains, suggesting concurrent immunosenescence. In the older group we identified 25 upregulated proteins whose elevated abundance, combined with acquired immune aging may constitute a plasma proteomic signature of aging. The degree of upregulation of these signature proteins varied among elderly subgroups with different life-experience. A good physical condition and/or cognitive function correlated with a lower expression of the aging-related proteomic profile. Furthermore, several sex-specific differences were identified in the plasma profiles of young donors. Reversely, among elderly individuals, no major differences were observed, except for an increased level of Pregnancy Zone Protein (PZP) in females.
    Conclusions: Proteomic analysis of plasma revealed protein variations associated with aging, primarily involving inflammation-related pathways, immunosenescence features, and sex-linked differences. This study highlights the pathological characteristics underlying the aging process.
    Keywords:  aging; immunity; inflammation; mass spectrometry; plasma; proteomics; senescence
    DOI:  https://doi.org/10.3389/fimmu.2025.1695213
  23. Nat Commun. 2026 Jan 21. 17(1): 770
    Spatiotemporal regulation of energetic charge dictates T cell function.
    Aleksandra S Chikina, Béatrice Corre, Fabrice Lemaître, Philippe Bousso.
      Immune cell functions are dictated by their differentiation state and regulated by transcriptional and epigenetic changes. Immune cell differentiation also controls the preferential metabolic pathways used for energy production. However, whether the energy charge of individual immune cells itself varies across time and space and regulates cell function remains to be fully understood. Here, we show that T cells harbor distinct energetic resources and function in different anatomical locations and times of the day. To monitor ATP: ADP ratio, an indicator of cellular energetic resources, we rely on SPICE-Met, a method that dissects energy metabolism in complex cell populations in vivo. We find that cells with the highest glycolytic capacity, including effector T cells and NK cells, exhibit the highest ATP: ADP ratio. Importantly, effector T cells but not naïve T cells display higher energetic charge when present in the blood compared to lymph nodes due to differential glucose availability. Energetic resources are also regulated in a circadian manner, being highest at the early rest phase. Importantly, differences in energetic charge are directly translated at the level of T cell function, impacting IFN-γ production. Thus, modulation of energetic charge and nutrient availability dictates immune cell function across time and space.
    DOI:  https://doi.org/10.1038/s41467-026-68559-1
  24. BMC Cancer. 2026 Jan 21. 26(1): 97
    Integrative transcriptomic profiling reveals subtype-specific therapeutic vulnerabilities and resistance mechanisms in prostate cancer.
    Wei Liu, Weiyu Kong, Silin Jiang, Yong Wei, Zijie Yu, Xiaoyang Cao, Jian Yang, Xiyi Wei, Luming Shen, Chao Qin, Qingyi Zhu.
       OBJECTIVE: Advanced prostate cancer (PCa) remains therapeutically challenging due to heterogeneous mechanisms of resistance to androgen receptor (AR)-targeting agents. While AR signaling persists in castration-resistant PCa (CRPC), emerging evidence suggests AR-independent survival pathways may contribute to therapeutic escape. This study integrates transcriptomic data and clinical profiling to dissect AR dependency and resistance mechanisms in PCa, aiming to identify subtype-specific vulnerabilities and therapeutic targets.
    METHODS: We performed CRISPR-Cas9 screens in AR-dependent (VCaP, LNCaP, 22Rv1) and AR-independent (DU145, PC-3, WPE1-NA22, P4E6, Shmac5) cell lines to identify core essential genes. RNA sequencing data from TCGA-PRAD, Changhai, and DKFZ cohorts were integrated to define molecular subtypes using consensus clustering. Spatial transcriptomics (ST) and single-cell RNA sequencing (scRNA-seq) were employed to validate gene expression patterns in primary tumors and metastatic samples. Temporal expression dynamics were analyzed using fuzzy clustering to identify resistance mediators, with a focus on MCL1. Drug sensitivity analysis revealed that AR-dependent cells were more sensitive to MCL1 inhibitor UMI-77, and MCL1 expression was higher in Enzalutamide-resistant cell lines. Functional validation via MCL1 knockdown confirmed its role in supporting the proliferation and inhibiting apoptosis of resistant cells.
    RESULTS: CRISPR screening identified 952 shared essential genes in prostate cancer, with 157 AR-high essential signature and 130 AR-low essential signature genes. AR-high essential signature genes enriched in cell cycle/polycomb pathways, while AR-low essential signature genes correlated with oxidative phosphorylation/mTOR signaling. Consensus clustering of TCGA-PRAD data revealed three molecular subtypes (Clusters 1-3); Cluster 3 showed worst prognosis (shorter PFI/OS) and advanced clinical features (higher T/N stage, Gleason grade). External validation confirmed Cluster 3's aggressive phenotype and independent prognostic value (meta-cohort HR = 1.98, 95% CI: 1.19-3.27). Cluster 3 signature genes were upregulated in metastatic/CRPC tissues and spatially enriched in CRPC epithelium. Notably, Cluster 3 shared essential gene expression decreased after Enzalutamide treatment, whereas AR-high essential signature genes remained stable. MCL1 emerged as a key resistance driver, demonstrating persistent upregulation in Enzalutamide-resistant cells and CRPC models.
    CONCLUSIONS: This study elucidates distinct AR dependency landscapes in PCa, revealing AR-independent survival pathways and a clinically actionable molecular subtype (Cluster 3) linked to therapy resistance. MCL1 emerges as a critical mediator of adaptive resistance, highlighting the need for combination therapies targeting both AR-driven and AR-independent programs to improve outcomes in advanced PCa.
    Keywords:  CRISPR-Cas9 screen; Enzalutamide resistance; MCL1; Multi-omics; Prostate cancer
    DOI:  https://doi.org/10.1186/s12885-025-15357-5
  25. Microbiome. 2026 Jan 21. 14(1): 37
    Commensal microbe-derived butyrate enhances T follicular helper cell function to boost mucosal vaccine efficacy.
    Haeun Ko, Chan Johng Kim, Seungyeon Choi, Jaegyun Noh, Seung Won Kim, Juhun Lee, Seohyun Byun, Haena Lee, John Chulhoon Park, Hye Eun Park, Amit Sharma, Minhyuk Park, Junghwan Park, Choong-Gu Lee, Kwang Hyun Cha, Sin-Hyeog Im.
       BACKGROUND: The gut microbiota plays an essential role in mucosal immunity, with secretory immunoglobulin A (IgA) acting as a key effector in neutralizing pathogens and maintaining host-microbiota homeostasis. IgA production occurs via T cell-dependent (TD) and -independent pathways, with T follicular helper (Tfh) cells driving high-affinity, antigen-specific IgA responses. However, the specific microbial taxa and metabolites that regulate Tfh-mediated IgA responses under steady-state conditions remain poorly understood. This study investigated how gut microbiota-derived signals shape Tfh responses and IgA production, with implications for enhancing mucosal vaccine efficacy.
    RESULTS: We demonstrate that Peyer's patches (PP)-derived Tfh cells exhibit superior IgA-inducing capacity compared to splenic Tfh cells. RNA sequencing revealed distinct transcriptional profiles in PP-Tfh cells, including upregulation of the genes associated with Tfh differentiation and activation (Bcl6, Cd40lg, Maf), T-B cell interactions (Il21, Sh2d1a, Fyn), and migration (Ccr6, Cxcr5). Functionally, PP-Tfh cells formed larger T-B cell contact areas and induced significantly higher IgA secretion in co-culture than their splenic counterparts. Microbiota depletion experiments revealed that eliminating neomycin-depleted bacteria reduced fecal IgA levels and diminished PP-Tfh cell frequencies. Fecal microbiota transplantation from neomycin-treated mice restored both IgA production and Tfh responses in germ-free (GF) mice. Bioinformatic analysis (PICRUSt2 and LEfSe) identified butyrate-producing Lachnospiraceae and Ruminococcaceae as key drivers of the Tfh-IgA axis. Butyrate supplementation enhanced Tfh differentiation and IgA⁺ germinal center B cell development in vitro and increased fecal IgA levels in vivo. Mechanistically, butyrate promoted IgA production via GPR43 signaling, as its effect was lost in co-cultures with Gpr43⁻/⁻ Tfh cells. Moreover, treatment with tributyrin, a butyrate prodrug, enhanced vaccine-induced IgA and protected mice against Salmonella Typhimurium infection, reducing bacterial burden and tissue damage. These findings define a functional microbiota-Tfh-IgA axis sustained by neomycin-depleted, butyrate-producing bacteria.
    CONCLUSIONS: Our study underscores the crucial role of the gut microbiota, particularly neomycin-depleted butyrate producing taxa, in regulating PP-Tfh cell function and IgA production. Butyrate emerges as a metabolite linking microbial metabolism to Tfh differentiation and IgA class switching. Together, these findings establish a microbiota-metabolite-Tfh cell axis essential for mucosal immune homeostasis and suggest novel strategies for enhancing vaccine efficacy and protection against enteric infections. Video Abstract.
    Keywords:   Salmonella Typhimurium; Butyrate; Gut microbiota; Immunoglobulin A; Mucosal immunity; Peyer’s patches; T follicular helper cell
    DOI:  https://doi.org/10.1186/s40168-025-02284-7
  26. Front Endocrinol (Lausanne). 2025 ;16 1720484
    The influence of immune regulation mediated by intestinal microbiota on postmenopausal osteoporosis and intervention strategies.
    Lili Wang, Shiqing Chen, Xiaoyu Cai, Yongquan Zheng, Caihong Zheng, Yao Yao.
      Postmenopausal osteoporosis (PMO) is a common metabolic bone disease characterized by reduced bone mass and deteriorated bone microarchitecture, leading to an increased risk of fractures. In recent years, growing evidence has highlighted the role of gut microbiota and its immune-mediated regulation in the pathogenesis and progression of PMO. The gut microbiota modulates host immune responses, influencing the balance between bone resorption and bone formation. Estrogen deficiency after menopause disrupts gut microbiota composition, induces systemic inflammation, and promotes osteoclast activation, accelerating bone loss. Moreover, specific microbial communities and their metabolites, such as short-chain fatty acids (SCFAs), regulate bone metabolism by modulating immune cells, including T cells, B cells, and macrophages. Various microbiota-targeted interventions, such as probiotics, prebiotics, and fecal microbiota transplantation (FMT), have shown potential in improving bone health. However, several challenges remain, including individual variability in microbiota composition, the long-term effects of interventions, and their clinical applicability. Further investigations into the gut microbiota-mediated immune regulation of PMO may provide novel insights and therapeutic strategies for osteoporosis prevention and treatment.
    Keywords:  PMO; bone metabolism; gut microbiota; immune regulation; intervention strategies
    DOI:  https://doi.org/10.3389/fendo.2025.1720484
  27. Eur J Prev Cardiol. 2026 Jan 20. pii: zwag004. [Epub ahead of print]
    Sex differences in ECGs of trained athletes: A systematic review and meta-analysis.
    Angus J Davis, Rheannon van der Linden, Sameera Mukhtar, Danica Sardelich, Simone Ungaro, Alessandro Zorzi, Bradley J Petek, Tochukwu Ilodibia, Ludmila Cosio-Lima, Wojciech Krol, Hamish MacLachlan, Belinda Gray, Tim Driscoll, Jessica J Orchard.
       AIMS: To describe and quantify sex differences in the screening electrocardiograms (ECG) of athletes.
    METHOD: Five databases (MEDLINE, EMBASE, Scopus, SPORTDiscus and Web of Science) were searched from inception until October 2024. Included studies were original research articles examining athletes aged 16-40 years, who had a 12-lead screening ECG, and where analysis was stratified by sex. Risk of bias was assessed using a validated tool. A meta-analysis was performed, using a random-effects model, assessing proportions of athlete normal, borderline and abnormal ECG features (according to the 2017 International Criteria) and several ECG measurements.
    RESULTS: Eighty-five cross-sectional studies were included. The studies comprised 19,069 female athletes (mean age 20.6±2.8 years) and 57,745 male athletes (mean age 21.3±3.1 years). Female athletes were more likely to have abnormal T-wave inversion (TWI) (OR 2.3, 95% CI: 1.5-3.5), and isolated TWIV1-V3 (OR 5.6, 95% CI: 3.2-9.9) compared to males. No female athletes and two male athletes with isolated TWIV1-V3 were diagnosed with a condition associated with sudden cardiac arrest or death (both male athletes diagnosed with arrhythmogenic cardiomyopathy). Female athletes were also more likely to have an abnormal ECG per the International Criteria, though the finding was not statistically significant (OR 1.3, 95% CI: 0.7-2.4). Female athletes had a 16ms (95% CI 4-27ms) longer QTc interval than male athletes.
    CONCLUSION: Compared to male athletes, female athletes were twice as likely to have abnormal TWI and six times as likely to have isolated TWIV1-V3, a finding which was not accompanied by diagnoses of cardiac pathology in female athletes. These data should help inform sex-specific aspects of athlete ECG screening guidelines.
    Keywords:  T-wave inversion; athlete; electrocardiogram; meta-analysis; preparticipation screening; sex differences
    DOI:  https://doi.org/10.1093/eurjpc/zwag004
  28. J Hum Reprod Sci. 2025 Oct-Dec;18(4):18(4): 239-245
    Luteinizing Hormone β-subunit Gene Polymorphisms and Androgen Levels are Less Predictive of Ovarian Response in Polycystic Ovary Syndrome In vitro Fertilisation Women: A Nested Case-Control Study.
    Irham Suheimi, Budi Wiweko, Rosalina Thuffi, Raden Muharam, Asmarinah, Wresti Indriatmi, Safarina G Malik, Arief Boediono, Syarief Thaufik Hidayat, Ivan Sini, Batara Sirait.
       Background: Genetic polymorphisms in the luteinizing hormone (LH) β-subunit gene have been associated with responses to controlled ovarian hyperstimulation (COH) in in vitro fertilisation (IVF) patients. Variants in rs1800447 and rs34349826 may increase androgen production, potentially impairing folliculogenesis and ovarian response.
    Aim: The aim of this study was to investigate the clinical significance of LH β-subunit single-nucleotide polymorphism (SNP) (rs1800447 and rs34349826), levels of testosterone, sex hormone-binding globulin (SHBG) and free testosterone index in predicting COH response in polycystic ovary syndrome (PCOS) women.
    Settings and Design: This nested case-control study enlisted 122 women with PCOS in the Morula IVF Jakarta Clinic, Jakarta, Indonesia.
    Materials and Methods: The selection of cases and controls was in the ratio of 1:2. Blood samples were taken on day 2 or 3 of menstrual cycle. Sanger sequencing was utilised to genotype the LH β-subunit genes (rs1800447 and rs34349826). Levels of testosterone and SHBG were measured to calculate the free testosterone index. Women were retrospectively grouped as hyporesponders (<8 oocytes) or normo/hyperresponders (≥8 oocytes) according to the number of retrieved oocytes.
    Statistical Analysis Used: SPSS Software version 21.0 (IBM Corp., USA). Independent t-test or Mann-Whitney test for numerical variables and Chi-square test for categorical variables were employed.
    Results: A unique automatic transmission (AT) variant in both rs1800447 and rs34349826 LH β-subunit was discovered, which has yet been reported previously. Notably, the proportion of heterozygous LH β genotypes (AT and AG) in both rs1800447 and rs34349826 was similar between hyporesponder and normo/hyperresponder groups (P > 0.05). All participants were normoandrogenic PCOS women, indicated by the normal level of testosterone (0.84 ± 0.35 nmol/L) and SHBG (57.87 ± 29.20 nmol/L) as well as free testosterone index (1.88 ± 1.34). No difference in testosterone levels, SHBG and free testosterone index was observed among the studied groups (P > 0.05).
    Conclusion: LH β gene SNPs (rs1800447 and rs34349826), testosterone level, SHBG level and free testosterone index were not significantly correlated and less effective clinical indicators for COH response in normoandrogenic PCOS women.
    Keywords:  Androgen; clinical relevance; in vitro fertilisation; luteinizing hormone β-subunit; polycystic ovary syndrome; polymorphisms
    DOI:  https://doi.org/10.4103/jhrs.jhrs_7_25
  29. Front Immunol. 2025 ;16 1747323
    Decidual stromal cells drive CD16+ macrophages towards an immunoregulatory phenotype via extracellular matrix-adhesion molecule interaction during early pregnancy.
    Hui-Li Yang, Jia-Wei Shi, Zhen-Zhen Lai, Xin Li, Chun-Jie Gu, Zi-Meng Zheng, Hong-Bo Zhao, Jiang-Feng Ye, Li Wang, Ting Peng, Ming-Qing Li.
       Introduction: Dramatic alterations of the extracellular matrix (ECM), which can regulate cell behavior by binding to adhesion molecules and are intrinsically linked to immune regulation, occur in decidualization during early pregnancy. Decidual macrophages (dMφ) are a group of tissue-resident cells with an affinity for adhesion. An interactive dialogue occurs between decidual stromal cells (DSCs) and dMφ, however it remains unclear whether this process is associated with ECM-adhesion molecules. This study was conducted to investigate the cross-talk of DSC and CD16+ dMφ via extracellular matrix-adhesion molecule interaction in early pregnancy.
    Methods: Single-cell sequencing data from endometrial and decidual tissues were analyzed to elucidate the interactions between DSCs and dMφ. We assessed the levels of ECM components in the decidua at the tissue or cellular levels, and examined the expression of adhesion molecules and polarization molecules in CD16+ or CD16- dMφ. Then we validated DSC-CD16+ Mφ interactions using the co-culture system. Finally, we evaluated the levels of ECM components in decidua and the expression of molecules in dMφ in patients with recurrent miscarriage (RM).
    Results: DSCs communicated with dMφ via ECM-adhesion molecules. Collagen IV, osteopontin (OPN) and hyaluronic acid (HA) derived from DSCs promoted the development of CD16+ dMφ and their differentiation toward an immunomodulatory phenotype via their receptors, which is beneficial for maintaining immune tolerance. In patients with RM, decidua exhibits weakened ECM-CD16+ dMφ regulatory link, which may be associated with the underlying pathogenesis.
    Discussion: This study confirms that DSC can regulate the immune status of CD16+ dMφ through the ECM-adhesion molecule axis, further elucidating the regulatory mechanisms of Mφ during decidualization. Exploration of therapeutic strategies based on ECM-receptor-mediated stroma-immune interactions holds promise as novel treatment approaches for miscarriage.
    Keywords:  CD16; decidual stromal cell; extracellular matrix; macrophage; miscarriage
    DOI:  https://doi.org/10.3389/fimmu.2025.1747323
  30. Curr Res Toxicol. 2026 ;10 100278
    Identifying androgen receptor antagonists using a metabolically competent high-throughput screening assay.
    Caitlin Lynch, Pranav Shah, Jinghua Zhao, Xin Xu, Ruili Huang, Menghang Xia.
      Androgen receptor (AR) is a nuclear receptor with a well-established role in sexual function and development. Modifications in AR can lead to endocrine disruption, cancer, and other diseases, making it imperative to identify compounds that influence these changes. AR modulators have been identified using immortalized cell lines in a high-throughput screening assay. However, most of these methods do not incorporate metabolism, leading to misclassification of compounds that normally require it to become AR modulators. Metabolism transforms exogenous parent compounds into metabolites that are easier to excrete, and normally less active than the parent. However, some metabolites modulate AR more effectively than the parent compound. Incorporating metabolism into a large compound screen can identify active metabolites as potential AR modulators. In this study, we optimized a high-throughput screening assay that included rat liver microsomes (RLM) as an exogenous metabolic system to detect AR antagonists. A robotic screen of the LOPAC library + 88 Tox21 compounds (a total of 1365 unique compounds) was then performed to validate the assay and identify any bioactivated AR modulators within the test library. Fifty-five compounds were identified as potential AR antagonists; 9 compounds out of these 55 compounds were found to have significant potency shifts between RLM free and RLM assays, suggesting the necessity of metabolism for their AR activity. A concurrent assay using heat-inactivated RLM was conducted to discern the true activity of each compound. Metabolic stability assays were also performed on the top compounds to clarify their ability to transition from parent to metabolite using RLM. Four compounds were identified as novel parent compounds requiring metabolism to become more potent AR antagonists. However, only 4,5-dianilinophthalimide (DAPH) displayed a clear concentration-response curve with a more potent IC50 when RLM was included compared to its parallel screens, identifying it as a true AR antagonist requiring metabolism.
    Keywords:  Androgen receptor; Metabolism; Quantitative high-throughput screening
    DOI:  https://doi.org/10.1016/j.crtox.2025.100278
  31. Front Immunol. 2025 ;16 1725702
    Regnase-1 in cDC1 controls T cell priming and shapes the dynamics of experimental autoimmune encephalomyelitis.
    Xingyu Rong, Hai Wang, Shintaro Muraoka, Takuya Uehata, Masanori Yoshinaga, Tsuneyasu Kaisho, Osamu Takeuchi.
       Introduction: Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system (CNS), in which various immune cells contribute to disease progression, yet the role of dendritic cells (DCs) remains incompletely understood. The RNA-binding protein Regnase-1 plays an important role in regulating immune cell function, but its function in DCs, particularly conventional type 1 DCs (cDC1), has not been defined.
    Methods: We investigated the role of Regnase-1 in cDC1 and its impact on experimental autoimmune encephalomyelitis (EAE) on Regnase-1 fl/+ Xcr1 -Cre+ and control mice.
    Results: Reduced Regnase-1 expression in cDC1 enhanced pro-inflammatory gene expression and increased their capacity to activate T cells. In the EAE model, Regnase-1 fl/+ Xcr1 -Cre+ mice displayed accelerated inflammatory progression during the acute phase, accompanied by increased infiltration of Th1 cells and activated CD8+ T cells in the CNS. Subsequently, Regnase-1 fl/+ Xcr1 -Cre+ mice showed accelerated recovery, together with increased frequencies of central memory CD8+ T (Tcm) cells.
    Discussion: Our study reveals the complex role for cDC1 with reduced Regnase-1 expression in inflammatory regulation, exacerbating inflammatory responses during the acute phase, while facilitate recovery. This dual role highlights Regnase-1 in cDC1 as a critical regulator that balances inflammation and immune memory.
    Keywords:  Regnase-1; autoimmune disease; conventional type I dendritic cells; inflammation; post-transcriptional regulation
    DOI:  https://doi.org/10.3389/fimmu.2025.1725702
  32. Eur J Med Res. 2026 Jan 19. 31(1): 95
    Correlation between ambulatory blood pressure indices and sex hormone imbalance in hypertensive women with different menopausal durations: a cross-sectional study.
    Sijie Zhang, Heng Yu, Chenyang Jing, Wei Liang, Lei Chen, Yurui Lin, Ruxuan Li, Jing Yu, Ningyin Li.
       BACKGROUND: The prevalence of hypertension in postmenopausal women increases significantly compared to premenopausal women and gradually catches up with, or even exceeds, that of their male counterparts. Imbalanced levels of sex hormones play a critical role in the elevation of blood pressure (BP) observed in this population. Furthermore, blunted nocturnal BP decline is a key factor contributing to their increased cardiovascular risk. This study compared ambulatory blood pressure (ABP) values between female hypertensive patients with different menopausal durations and matched male patients, aiming to explore the correlation between sex hormone imbalance and ABP values.
    METHODS: This cross-sectional study included 210 postmenopausal women and 210 matched male patients. The male patients were matched to hypertensive female patients with varying menopausal durations on the basis of variables such as age, body mass index (BMI, kg/m2), hypertension duration, antihypertensive medication use and metabolism-related indicators. Clinical characteristics, Ambulatory Blood Pressure Monitoring (ABPM), and sex hormone levels were evaluated. Quantitative data were analyzed using one-way analysis of variance and multiple regression analysis.
    RESULTS: Compared with matched men, in women with hypertension within 5 years after menopause, the T/PRL-E2 was associated with nighttime SBP. In those with menopausal durations of 6-10 years, the FSH/T ratio is associated with the absence of significant differences in 24-h SBP and daytime SBP relative to matched men, while the PRL/FSH ratio is negatively correlated with nighttime SBP in this group. In hypertensive women with menopausal durations of 11-15 years, the PRL-E2/T ratio is linked to 24-h, daytime and nighttime SBPs. In contrast, correlations involving diastolic blood pressure (DBP) indices displayed a distinct pattern. The FSH/PRL ratio shows a protective association with all mean DBP parameters in hypertensive women with menopausal durations less than 5 years and 11-15 years, whereas the T/P ratio is positively associated with those with 6-10 years of menopause.
    CONCLUSIONS: There was a significant correlation between sex hormone levels and ABP parameters, particularly nocturnal SBP, in women with different menopausal durations.
    TRIAL REGISTRATION: This study was retrospectively registered on ClinicalTrials.gov (NCT03451747) on February 18, 2018.
    Keywords:  Hypertension; Menopausal duration; Nocturnal blood pressure; Postmenopause; Sex hormone
    DOI:  https://doi.org/10.1186/s40001-025-03797-5
  33. Nat Commun. 2026 Jan 21.
    Women with polycystic ovary syndrome exhibit impaired endometrial receptivity with excessive ERα and histone lactylation.
    Hongying Shan, Yue Wang, Baoying Liao, Kai-Lun Hu, Xiunan Chen, Chenxi Xiao, Zi Yang, Fenting Liu, Tianliu Peng, Mingmei Lin, Feng Deng, Ping Zhou, Yang Yu, Rong Li, Heng Pan.
      Polycystic ovary syndrome (PCOS) is one of the most common reproductive disorders in women and severely impairs fertility. Extant clinical studies can only provide indirect and plausible evidence to support endometrial dysfunction as an ovary-independent contributor to PCOS infertility, considering heterogeneous confounders in their phenotypes, comorbidities, and severities. By strictly controlling embryonic factors and potential confounders, our retrospective cohort study reports an adverse implantation rate in women with PCOS, confirming abnormalities in the endometrium, which are accompanied by excessive ERα and histone lactylation. Next, we validate the cooccurrence of impaired uterine receptivity with elevated ERα and histone lactylation in the PCOS mouse model. Inhibiting histone lactylation could downregulate ERα and estrogen-responsive genes, restore uterine receptivity, and improve the implantation rate in PCOS mice. Here, we show that upregulated ERα and histone lactylation are key indicators of impaired endometrial receptivity in PCOS, providing a potential therapeutic strategy by inhibiting lactate production.
    DOI:  https://doi.org/10.1038/s41467-026-68441-0
  34. NPJ Precis Oncol. 2026 Jan 21.
    Single nuclei and spatial profiling of sacrococcygeal teratomas reveals cellular composition and X inactivation heterogeneity.
    Ernesto J Rojas, Krinio Giannikou, Benjamin J Huang, Soo-Jin Cho, Marco A Cordero, Deion Pena, Lan Vu, Aditya Bagrodia, S Christopher Derderian, Tippi C MacKenzie, Diana J Laird.
      Sacrococcygeal teratomas (SCTs) are the most common neonatal tumors, yet their cellular origins, clinical stratification, and sex bias-occurring three times more in XX than XY individuals-remain poorly understood. To address these gaps, we examined six postnatal (one male and five female) and two prenatal (both female) SCTs by single nuclei RNA-seq and spatial transcriptomics. We identified five broad cellular lineages in SCTs: stroma, epithelia, endothelia, neuroectoderm, and immune. The transcriptomes and lineage compositions showed significant heterogeneity, which offer a framework for future molecular stratification. SCTs are thought to originate from and be propagated by pluripotent cells, notably however, we did not detect these populations. Among female tumors, a subset of cells exhibited biallelic expression of X-linked genes, consistent with X-inactivation failure or reactivation of the once inactivated X-chromosome. These biallelic cells were enriched for developmental and neuronal programs, whereas cells with single-allelic X-chromosome preferentially expressed immune-related genes. Biallelic X-chromosome activation, which can occur only in female cells, may result in transcriptomic features that favor survival of tumor cells, contributing to the sex bias of SCTs. Our findings reveal a link between X-chromosome inactivation and SCT cell identity, suggesting that X-dosage dysregulation may influence SCT heterogeneity and immune landscape.
    DOI:  https://doi.org/10.1038/s41698-025-01262-4
  35. Cell Rep. 2026 Jan 19. pii: S2211-1247(25)01637-7. [Epub ahead of print]45(1): 116865
    IL-18 produced by pregnant uterus promotes essential inflammatory responses and fetoplacental growth.
    Hajime Ino, Yasuyuki Negishi, Yumi Horii, Eri Koike, Richard A Flavell, Shunji Suzuki, Rimpei Morita.
      Placental insufficiency affects fetomaternal health throughout life. Although the interaction between the maternal uterine immune milieu and fetus-derived cells plays a crucial role in placental formation, several aspects remain unclear. Therefore, we conducted this study to investigate the effects of interleukin (IL)-18, a distinctive cytokine with both proinflammatory and anti-inflammatory properties, on the uterine immune milieu and placental development. Our results identified pregnant uterine smooth muscle cells as an important source of IL-18, which supports homeostatic type 1 immune responses. IL-18 facilitates appropriate placental development through uterine vascular remodeling and placental angiogenesis. Smooth muscle cell-specific Il18 knockout dam mice exhibited excessive cytotoxicity of uterine natural killer (NK) cells, impaired fetoplacental growth, and elevated maternal blood pressure, reflecting preeclampsia-like phenotypes. Their offspring demonstrated a tendency toward excessive weight gain and delayed neurodevelopment. Overall, this study emphasizes the essential role of IL-18 in placental formation and its wider implications for fetomaternal health.
    Keywords:  CP: developmental biology; CP: immunology; NK cells; angiogenesis; fetal growth restriction; interleukin-18; mouse model; placenta; preeclampsia; pregnancy; reproductive immunology; uterus
    DOI:  https://doi.org/10.1016/j.celrep.2025.116865
  36. Am J Reprod Immunol. 2026 Jan;95(1): e70211
    Gut Microbiota Changes After Hormonal or Surgical Treatment for Endometriosis.
    Yosuke Ono, Osamu Yoshino, Takeshi Sasayama, Masami Ito, Tatsuya Yoshihara, Kota Tanaka, Akiko Nakagomi, Satoko Sasatsu, Maki Ogi, Hikaru Tagaya, Tomohiko Fukuda, Takeshi Nagamatsu, Takuji Yamada.
       PURPOSE: Although studies have suggested a link between gut microbiota and endometriosis pathophysiology, the effects of treatment for endometriosis remain unclear.
    METHODS: In this prospective observational study, 27 patients with stage III/IV endometriosis and 17 healthy controls provided a total of 56 fecal samples. In endometriosis patients, gut microbiota profiles were analyzed before and after hormonal therapy or surgery to assess treatment-related changes. 16S rRNA gene sequencing was used for microbiota analysis.
    RESULTS: No differences in α- or β-diversity were observed between the endometriosis and control groups, although patients with endometriosis had high levels of Acidaminococcus, Lachnoclostridium, and Paraprevotella and low levels of Odoribacter (all p < 0.05). Among the eight patients who received hormonal therapy, no significant changes in α- and β-diversity were observed between the pre- and post-treatment samples. A comparison of samples from the same individuals showed an increase in Blautia, which is associated with mental health stability, and a decrease in Sutterella, which is involved in regulating the intestinal barrier. In an exploratory analysis of patients without recurrence after surgery (n = 4), α-diversity significantly increased (p = 0.035), with stable β-diversity. Postsurgical increases were observed in 10 genera, including six inflammation-related taxa; five (Flavonifractor, [Eubacterium]_brachy_group, Hungatella, Incertae_Sedis, and Fournierella) are associated with anti-inflammatory effects.
    CONCLUSIONS: Hormonal therapy for endometriosis may help not only to control lesions but also to support mental health. Surgical treatment may alter the composition of inflammation-associated gut bacteria; however, these exploratory results from a small cohort should be interpreted with caution. Further studies with larger sample sizes are warranted.
    Keywords:  Blautia; Flavonifractor; endometriosis; hormone therapy; inflammation; mental health; microbiota; α‐diversity
    DOI:  https://doi.org/10.1111/aji.70211
  37. Proc Natl Acad Sci U S A. 2026 Jan 27. 123(4): e2518703123
    A sexually dimorphic neuronal cluster in the mouse medial amygdala responds to male sexual status.
    Tamar Licht, Adan Akarieh, Aya Dhamshy, Amit Zeisel, Osnat Ophir, Dan Rokni.
      Increasing scientific interest has been directed toward understanding sexual dimorphism in the brain. Although several brain structures exhibit masculine or feminine characteristics, strictly binary anatomical feature, comparable to those observed in genitalia, has been rarely identified. In this study, we identified a dense, sexually dimorphic cluster of neurons in the posterodorsal medial amygdala (MeApd), which we named DIMPLE (Dimorphic IEGs Medial Posterodorsal amygdala Labeled Ensemble) that exhibited a remarkable binary pattern of c-fos promoter activation. Using the TRAP2 (Targeted Recombination in Active Populations) transgenic mouse model, we found that it was consistently labeled in all females, regardless of age or sexual experience. In contrast, DIMPLE labeling was absent in adult virgin males but present both prior to weaning and following mating. Surgical removal of gonads (ovariectomy or orchiectomy) did not alter the labeling pattern of DIMPLE in either sex. Interestingly, a single intraperitoneal injection of prolactin, a hormone that increases in males after mating, induced DIMPLE labeling in virgin males. However, treatment with cabergoline, a potent inhibitor of prolactin secretion, did not prevent DIMPLE labeling in females or in postmating males. Given the established role of the MeApd in social and reproductive behaviors, we hypothesize that DIMPLE may support neural mechanisms underlying female-typical behavior and potentially contribute to postmating behavioral shifts in males.
    Keywords:  c-Fos; medial amygdala; prolactin; sexual dimorphism
    DOI:  https://doi.org/10.1073/pnas.2518703123
  38. J Appl Microbiol. 2026 Jan 22. pii: lxag024. [Epub ahead of print]
    Vaginal Lactobacillus postbiotics ameliorate Gardnerella vaginalis-induced bacterial vaginosis by regulating vaginal microbiota and restoring Th17/Treg balance.
    Shuxin Zhou, Xin Wen, Weihua Chu.
       AIMS: Vaginal health is crucial to a woman's overall well-being. Bacterial vaginosis, a common gynecological condition resulting from dysbiosis, remains a significant clinical challenge. This study aims to investigate whether postbiotics derived from vaginal Lactobacillus strains exhibit therapeutic effects against bacterial vaginitis.
    METHODS AND RESULTS: Postbiotics, consisting of inanimate microorganisms and/or their components, were analyzed and found to contain lactic acid and acetic acid as the primary acidic constituents. In a model of G. vaginalis-induced bacterial vaginosis, postbiotics demonstrated enhanced antibacterial and antioxidant activities. They significantly alleviated clinical symptoms, modulated the composition of the vaginal microbiota, and increased microbial diversity. Specifically, postbiotics reduced the abundance of endotoxin-producing Escherichia-Shigella and Enterobacteriaceae, while promoting beneficial bacteria such as Muribaculaceae, Lachnospiraceae, and Streptococcus. Additionally, postbiotic treatment restored the balance between Th17 and Treg cells and regulated associated inflammatory factors.
    CONCLUSIONS: These findings indicate that postbiotics improve bacterial vaginitis through multiple mechanisms, including antibacterial and antioxidant effects, immune regulation, and restoration of vaginal flora structure and metabolic balance. This study highlights the potential clinical value of postbiotics in the treatment of bacterial vaginosis.
    Keywords:  Th17/Treg cell balance; bacterial vaginosis; postbiotics; vaginal microbiota
    DOI:  https://doi.org/10.1093/jambio/lxag024
  39. J Nutr. 2026 Jan 16. pii: S0022-3166(26)00015-5. [Epub ahead of print] 101366
    Maternal microbiota and its potential implications for mammalian reproduction health.
    Xinyu Lei, Yulian Zheng, Yuwen Chen, Jiayan Jiang, Guoxun Chen, Qianhong Ye.
      Microbiota-host crosstalk has an important role in maintaining metabolic homeostasis and regulating reproductive endocrine functions. However, the effects of maternal microbiota in reproduction and their underlying mechanisms have not been fully understood. Here, we systematically reviewed the regulation of maternal microbiota on maintaining steroid hormones synthesis, relieving reproductive organ disorders, and improving the follicular and fetal development. Moreover, the molecular mechanisms including the nutritional modulation of maternal microbiota on pregnancy outcomes and offspring growth were also discussed. In summary, maternal microbiota contributes to reproductive organs health and embryonic and fetal development, leading to profound impacts on offspring growth. These insights provide new opportunities to develop strategies aimed at optimizing maternal microbiomes to improve reproductive performance in mammals.
    Keywords:  Microbiota; fetal development; genital health; reproductive performance; steroid hormones
    DOI:  https://doi.org/10.1016/j.tjnut.2026.101366
  40. Cell Rep. 2026 Jan 21. pii: S2211-1247(25)01643-2. [Epub ahead of print]45(2): 116871
    Early-life microbiota skews long-term gene expression and chromatin states of bone marrow hematopoietic precursors.
    Ahmed K Kabil, Alissa Cait, Lisa A Reynolds, Sameeksha Chopra, Misha Bilenky, Michelle Moksa, Yicong Li, Jessica Cait, Diana Canals Hernaez, R Wilder Scott, Emily Fogarty, B Brett Finlay, William W Mohn, Martin Hirst, Michael R Hughes, Kelly M McNagny.
      Early life is a critical window during which the gut microbiota sculpts immunity and long-term susceptibility to allergic disease. Using neonatal antibiotic administration and bone marrow transplantation assays, we show that depletion of short-chain fatty acid (SCFA)-producing bacteria alters gene expression in hematopoietic stem and progenitor cells (HSPCs) and imprints a persistent, transplantable atopic immune phenotype. Bone marrow transplants from exposed mice generate recipients with elevated serum immunoglobulin E (IgE), downstream increased IgE bound to basophils, and exacerbated allergic lung inflammation following papain challenge. Depletion of SCFA-producing bacteria also impairs recovery from chemotherapy-induced myelosuppression and increases DNA damage in long-term HSPCs in an antibiotic-specific manner. Histone 3 lysine 27 (H3K27) chromatin immunoprecipitation sequencing (ChIP-seq) analyses further reveal differential histone acetylation in HSPCs, consistent with an SCFA-mediated epigenetic regulatory mechanism. Collectively, these findings establish a link between gut microbiota composition, hematopoiesis, and long-term immune function, offering a mechanistic explanation for microbiota-driven susceptibility to atopic disease and hematopoietic dysfunction.
    Keywords:  CP: Microbiology; CP: Stem cell research; allergic lung inflammation; bone marrow transplant; butyrate; early-life gut microbiota; epigenome; fecal microbiota transplantation; gut microbiome; hematopoietic stem and progenitor cells; immune development; short-chain fatty acids
    DOI:  https://doi.org/10.1016/j.celrep.2025.116871
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