bims-simsho Biomed News
on Systems immunology and sex hormones
Issue of 2026–02–08
forty-two papers selected by
Chun-Chi Chang, Lunds universitet
  1. Single-Cell RNA Sequencing Reveals Commensal Microbes Amplify Sex-Specific Immune Programming in the Murine Lung.
  2. Knowledge gaps and research priorities to understand sex differences in immunity.
  3. Sexual dimorphism in cancer: molecular mechanisms and precision oncology perspectives.
  4. Reduced glycoprotein hormone β-5 links male aging and testosterone decline to increased adiposity.
  5. Hippocampal estrogen levels, receptor types, and epigenetics contribute to sex-specific memory vulnerabilities to concurrent acute stresses.
  6. Transforming Growth Factor β1 Modulates Sex Differences in Cardiac Myofibroblast Activation on Hydrogel Biomaterials.
  7. Disruption of androgen receptor-cofactor interactions by the RNA-binding protein FUS/TLS alters androgen signalling in prostate cancer.
  8. The impact of age on clinical features and fertility outcomes in patients with polycystic ovary syndrome: a secondary analysis based on the PCOSAct trial.
  9. Motor unit discharge properties are modestly influenced by menstrual cycle-related fluctuations in sex hormone concentrations.
  10. Sex Hormones Differentially Modulate Ochratoxin A-Induced Nephrotoxicity in Female Rats.
  11. Sex differences in gut microbiota composition, function, and assembly in the plateau zokor (Eospalax baileyi).
  12. A review of estrogens used in menopausal hormone therapy.
  13. Sex Chromosomes and Gonadal Sex Interactions in Airway and Immune Responses to Allergen Challenge.
  14. From gut dysbiosis to decidual hostility: the immuno-metabolic crosstalk driving recurrent pregnancy loss.
  15. Correction: Lysine methyltransferase SMYD2 enhances androgen receptor signaling to modulate CRPC cell resistance to enzalutamide.
  16. Contribution of endometrial microbiome to inflammation-mediated infertility in women undergoing ART.
  17. Sex-specific gonadal transcriptome during early development of Siberian sturgeon.
  18. Distinct macrophage uptake of engineered and biological particles driven by host age and sex.
  19. The interactions between autophagy and immune in the liver-adipose-ovary circuit of polycystic ovary syndrome.
  20. The Biosocial Microbiome: Gender Identity, Geography, and Mucosal Microbial Phenotypes.
  21. The gut-heart axis in coronary artery disease: a scoping and narrative review of sex-based microbial and metabolic disparities.
  22. Sex-specific nonlinear DNA methylation aging trajectories reveal biomarkers of cancer risk and inflammation.
  23. Neuroglial Function and Hormonal Modulation in Neurodegenerative Diseases: The Influence of Sex Hormones.
  24. Aberrant Progesterone Receptor (PGR) expression is associated with Estrogen Receptor 1 (ESR1) expression in the endometrium from infertile women with endometriosis.
  25. Testosterone Replacement Therapy in Prostate Cancer Survivors Treated with Radiation with and without Androgen Deprivation Therapy: A Retrospective Study and Narrative Review.
  26. Estrogenic control of germ cell differentiation in medaka: independence of early sex dimorphism from zygotic estrogen and receptor signaling.
  27. Estrogen Receptor Alpha Determines Sex-Specific Cardiorespiratory and Autonomic Responses to Intermittent Hypoxia in Mice.
  28. Male-biased Yap1-Cd276/B7-H3 axis for immune evasion in medulloblastoma.
  29. Comprehensive 16S rRNA gene sequencing and meta-transcriptomic analyses of the female reproductive tract microbiota: two molecular profiles with different messages.
  30. Evolutionary dynamics of dosage compensation and sex-biased gene expression in morabine grasshopper Vandiemenella viatica.
  31. Follicular Fluid Oxidative Stress and Antioxidant Defense in Relation to Maternal Age, Ovarian Reserve, and In Vitro Fertilization Outcomes.
  32. Resource landscape shapes the composition and stability of the human vaginal microbiota.
  33. Not all vaginal microbiomes are equal: functional context shapes immune landscapes.
  34. Metabolic reprogramming tailors T cell immunity in sepsis.
  35. Sex Differences in Associations Between Adversity and Biological Ageing.
  36. Multi-omics elucidation of Lactiplantibacillus plantarum NKK20 in preventing PCOS via the gut-ovary axis: SCFAs-mediated microbiota-metabolite-immune crosstalk.
  37. Differential gene expression profiling of ectopic endometrium reveals key molecular pathways in endometriosis pathogenesis.
  38. Sex-specific differences in chronic rhinosinusitis with nasal polyps: toward more personalized management.
  39. Maternal fructose consumption differentially programs the allergic airway response in male and female mouse offspring.
  40. The estrogen-progestogen-oxidative stress network in uterine fibroids: mechanistic insights and therapeutic opportunities.
  41. Hybrid female sterility due to cohesin protection errors in mouse oocytes.
  42. γδ T cell-derived IL-4 initiates CD8+ T cell immunity.
  1. bioRxiv. 2026 Jan 24. pii: 2026.01.22.700627. [Epub ahead of print]
    Single-Cell RNA Sequencing Reveals Commensal Microbes Amplify Sex-Specific Immune Programming in the Murine Lung.
    Alexandra Melton, Krista Ferrari, Joseph P Hoffmann, Kejing Song, Jay K Kolls, Janet E McCombs.
      Sex-based differences in respiratory disease outcomes are well recognized. However, the underlying immunological mechanisms driving this dimorphism remain incompletely understood. While sex hormones influence immune cell development and function, the role of commensal microbes in shaping sex-specific lung immunity has not been explored. Here, we used single-cell RNA sequencing (scRNAseq) and flow cytometry to profile lung immune cells in male and female mice housed under specific pathogen-free (SPF) or germ-free (GF) conditions. Under SPF conditions, males exhibited a striking myeloid bias, with increased monocytes and macrophages, along with broad upregulation of inflammatory mediators, including S100a8, S100a9, and Il1b, across multiple cell types, and enrichment of TNF and interferon (IFN) signaling pathways. In contrast, females displayed lymphocyte-skewed profiles, with higher frequencies of T cells and natural killer (NK) cells. Interestingly, these sex-based differences in immune composition and inflammatory programs were largely absent in GF mice, indicating that microbial exposure amplifies baseline immunological dimorphism between males and females. Notably, select sex-associated features, including female-biased NK cell enrichment, persisted irrespective of microbial status, suggesting intrinsic, microbiota-independent programming. Together, these findings indicate that commensal microbes modulate sex-specific lung immunity by amplifying pre-existing intrinsic differences, highlighting the intersection of extrinsic (microbial) and intrinsic (sex-linked) factors in shaping baseline mucosal immunity.
    DOI:  https://doi.org/10.64898/2026.01.22.700627
  2. PLoS Biol. 2026 Feb;24(2): e3003578
    Knowledge gaps and research priorities to understand sex differences in immunity.
    Katie L Flanagan, Sabra L Klein.
      Differences in immunity in males and females throughout the life span manifest as differences in susceptibility to chronic diseases, infections, cancer, and responses to therapeutic interventions such as immunomodulatory drugs and vaccines. Sex steroids and sex chromosome-linked immune response genes have major roles in driving these differences, but the cells and signaling pathways governing these are disease-specific and often not known. Such knowledge is required to better understand sex differences in disease incidence and clinical course, and to provide treatments tailored to sex-divergent pathways underlying specific diseases. This Essay explores the major areas where further research is required to determine sex-differential mechanisms.
    DOI:  https://doi.org/10.1371/journal.pbio.3003578
  3. Biol Sex Differ. 2026 Feb 03.
    Sexual dimorphism in cancer: molecular mechanisms and precision oncology perspectives.
    Zhen Wang, Hanwen Hu, Yunjia Bao, Guohong Ren, Chenghui Yang.
      Sex differences play a crucial role in determining tumor incidence, treatment sensitivity, and prognosis among men and women. However, current clinical cancer treatment strategies fail to account for these differences. Furthermore, the underlying mechanisms of tumor disparities between sexes remain elusive. Sex differences in sex chromosomes, hormone levels, metabolism, and immunity synergistically contribute to tumor-related disparities. As the demand for precision medicine escalates, there is an urgent need to conduct further exploration and research to address the tumor differences between sexes. In this review, we discuss the impact of biological sex differences on tumor cells and the tumor microenvironment, aiming to identify more effective strategies for tumor prevention and treatment.
    Keywords:  Cancer; Sex chromosomes; Sex differences; Sex hormones; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s13293-026-00843-7
  4. J Clin Invest. 2026 Feb 03. pii: e192355. [Epub ahead of print]
    Reduced glycoprotein hormone β-5 links male aging and testosterone decline to increased adiposity.
    Gengmiao Xiao, Aijun Qian, Zhuo Gao, Tingting Dai, Hui Liang, Shuai Wang, Mulan Deng, Yunjing Yan, Xindan Zhang, Xuedi Zhang, Yunping Mu, Jiqiu Wang, Aibo Gao, Huijie Zhang, Fanghong Li, Allan Zijian Zhao.
      Aging commonly causes decline of testosterone or estrogen, leading to overaccumulation of fatness in males or females, respectively. Although such phenomenon can be readily explained by estrogen's direct action on adipocytes in females, accumulative evidence does not support the direct action of testosterone in adipocyte lipid metabolism, suggesting that there is a missing intermediary link. Herein, we propose that glycoprotein hormone β5 (GPHB5) is the intermediary linkage between testosterone and the regulation of adiposity. In clinical samples, blood levels of GPHB5 were correlated negatively with men's ages, and positively with circulating testosterone. Testosterone directly stimulated the expression of GPHB5 in cultured cells, pharmacological blockade of androgen receptor (AR) functions abrogated such effect. Knockout of AR led to not only development of obesity but also reduction of GPHB5 expression. Genetic ablation of GPHB5 in the males, but not in the females, lowered the browning of white adipose tissue, diminished energy expenditure and caused severe obesity. Importantly, elevated blood testosterone didn't exert its catabolic actions in GPHB5 null mice, and yet, recombinant GPHB5 protein was able to stimulate energy expenditure and reduce adiposity. Taken together, these results provided the strong proof that GPHB5 is the "missing" intermediary hormone linking testosterone (and aging) and its well-known catabolic effect on adipose tissue.
    Keywords:  Adipose tissue; Aging; Endocrinology; Metabolism; Obesity; Sex hormones
    DOI:  https://doi.org/10.1172/JCI192355
  5. Neuron. 2026 Feb 03. pii: S0896-6273(25)00993-6. [Epub ahead of print]
    Hippocampal estrogen levels, receptor types, and epigenetics contribute to sex-specific memory vulnerabilities to concurrent acute stresses.
    Rachael E Hokenson, Kiara L Rodríguez-Acevedo, Yuncai Chen, Annabel K Short, Sara A Samrari, Brinda Devireddy, Brittany J Jensen, Julia J Winter, Christine M Gall, Kiran K Soma, Elizabeth A Heller, Tallie Z Baram.
      It is increasingly recognized that acute traumatic events (e.g., mass shootings, natural disasters) can provoke enduring episodic memory deficits and generalization of trauma cues, and these are more common in women. We investigated the mechanisms and sex differences in memory vulnerability to multiple acute concurrent stresses (MACSs) in mice, focusing on the sex hormone 17β-estradiol and its receptors in the hippocampus. Surprisingly, high physiological hippocampal estradiol levels, observed in proestrus females and males, were required for MACS-induced episodic memory disruption and sensitization and generalization of stress cues. High estradiol levels were associated with permissive chromatin states in stress-vulnerable mice, while chromatin permissiveness and hippocampal estradiol were low in stress-resilient estrus females. Estrogen receptor (ER)β activation in resilient estrus females increased chromatin permissiveness and enduring vulnerability to MACSs, while ERα mediated milder stress-induced memory disruptions in males. Thus, hippocampal estradiol levels and sex modify chromatin states to enable long-lasting memory vulnerabilities to MACSs.
    Keywords:  PTSD; chromatin state; epigenetics; estradiol; estrogen; memory; receptor; sex differences; stress; women's health
    DOI:  https://doi.org/10.1016/j.neuron.2025.12.037
  6. bioRxiv. 2026 Jan 20. pii: 2026.01.16.699818. [Epub ahead of print]
    Transforming Growth Factor β1 Modulates Sex Differences in Cardiac Myofibroblast Activation on Hydrogel Biomaterials.
    Mason N Faust, Ashley K Nguyen, Rayyan M Gorashi, Nicole E Félix Vélez, Meaghan C Loud, Brian A Aguado.
      Cardiac fibrosis is a pathological process in which the myocardium stiffens due to the overproduction of extracellular matrix (ECM) proteins. Cardiac fibroblasts activate to myofibroblasts in response to the inflammatory cytokine transforming growth factor beta1 (TGF-β1) to promote fibrotic scarring. Biological sex also influences cardiac fibrosis progression and patient outcomes, where males exhibit increased fibrotic scarring after acute inflammation relative to females. At the cellular level, sex differences in TGF-β1-mediated cardiac myofibroblast activation processes have not been clearly defined. We hypothesized that TGF-β1 would cause sex-specific cardiac myofibroblast activation levels and alter the secretion of bioactive molecules to modulate sex differences in cardiac fibrosis. Primary left ventricle cardiac fibroblasts were isolated from male and female C57BL/6J mice and cultured on hydrogel biomaterials mimicking native myocardial ECM stiffness and treated with TGF-β1 and/or the TGF-β1 receptor inhibitor SD208. Male myofibroblasts exhibited increased α-SMA stress fiber formation, increased SMAD2/3 localization, and greater resistance to SD208 inhibition compared to female myofibroblasts on hydrogels at various time points tested. Sex differences in relative secreted cytokine abundance were also determined, with male CFs secreting increased vascular endothelial growth factor (VEGF) and female CFs producing increased periostin and fibroblast growth factor 21 in response to TGF-β1. Our findings establish that TGF-β1 mediates sex differences in cardiac myofibroblast activation on hydrogels and secreted factors that may modulate the myocardial microenvironment. Our work underscores the importance of using hydrogels as cell culture platforms to recapitulate sex-specific cardiac fibrosis phenotypes as a steppingstone towards identifying sex-dependent therapeutic interventions for cardiac fibrosis.
    DOI:  https://doi.org/10.64898/2026.01.16.699818
  7. Oncogene. 2026 Feb 06.
    Disruption of androgen receptor-cofactor interactions by the RNA-binding protein FUS/TLS alters androgen signalling in prostate cancer.
    G N Brooke, D A Leach, R L Culley, A Azadova, L Latonen, E Rees, M A Alkheilewi, A C Pine, F M Fioretti, C S Reader, S M Powell, V Reebye, J Waxman, T Visakorpi, C L Bevan.
      Prostate cancer is dependent upon the androgen receptor (AR), the activity of which is modified by cofactors that either enhance or repress its activity, often in a context-dependent manner. FUS/TLS is a multifunctional protein known to be important in multiple cancer types; in prostate cancer, we previously showed that FUS has a potential tumour suppressor role. Here, transcriptomic analysis of the LNCaP prostate cancer cell line shows a significant overlap in genes regulated by FUS and the androgen receptor. We demonstrate that FUS can regulate androgen receptor activity, in either direction, but predominantly represses androgen signalling. Reporter assays and domain-specific analyses of FUS identified mechanisms by which FUS modifies androgen receptor activity. FUS interacts with the androgen receptor and other cofactors to repress transcription; ChIP assays suggest that repression occurs via disassembly of the transcriptional complex. Quantitative proteomics and RNA-Seq were used to investigate FUS expression in patient samples across prostate cancer stages. FUS was found to be down-regulated in primary tumours, but up-regulated in advanced aggressive stages. These findings suggest that in early prostate cancer, FUS represses AR activity and tumour progression, leading to its down-regulation. In contrast, increased FUS expression in advanced disease appears to be linked to a loss of AR regulatory control.
    DOI:  https://doi.org/10.1038/s41388-026-03682-3
  8. Front Endocrinol (Lausanne). 2025 ;16 1697014
    The impact of age on clinical features and fertility outcomes in patients with polycystic ovary syndrome: a secondary analysis based on the PCOSAct trial.
    Fengjuan Lu, Hong Yu, Jiaxing Feng, Yang Liu, Hang Ge, Baichao Shi, Muxin Guan, Hongli Ma, Yu Wang, Jing Cong, Wen Yang, Conghui Han, Jingshu Gao, Xiaoke Wu.
       Objective: This study aimed to investigate age-related variations in baseline characteristics and reproductive outcomes among women with polycystic ovary syndrome (PCOS).
    Methods: A secondary analysis of the PCOSAct trial included 936 participants stratified into four age groups: 20-24, 25-29, 30-34, and 35-40 years. Differences in anthropometric measures, sex hormones, metabolic parameters, and pregnancy outcomes were analyzed using correlation and multiple logistic regression.
    Results: With increasing age, linear trends revealed increases in hirsutism score, systolic blood pressure, triglycerides, dyslipidemia, metabolic syndrome, and atherogenic indices (P-trend<0.05). Conversely, luteinizing hormone (LH), LH/FSH ratio, total testosterone, free testosterone, anti-Müllerian hormone (AMH), and HDL levels decreased (P-trend<0.05). Age independently correlated with these metabolic and endocrine shifts (all P<0.05). Advanced age was associated with higher ovulation induction success (adjusted OR = 1.058, 95% CI:1.006-1.114, P = 0.030) but also an increased risk of first-trimester threatened abortion (adjusted OR = 1.11, 95% CI:1.009-1.210, P = 0.031). No significant associations were observed with clinical pregnancy or live birth.
    Conclusion: The clinical presentation of PCOS evolves significantly with advancing age. It is typically characterized by a shift from a state of hyperandrogenism and reproductive abnormalities in younger women to a profile increasingly dominated by progressive metabolic disturbances and cardiovascular risks in later years. Although ovulation response improves in older patients, they face a higher risk of early pregnancy loss. This underscores the necessity of implementing age-stratified clinical management for individuals with PCOS.
    Keywords:  age; endocrine; metabolic disorders; polycystic ovary syndrome; reproductive outcomes
    DOI:  https://doi.org/10.3389/fendo.2025.1697014
  9. bioRxiv. 2026 Jan 20. pii: 2026.01.16.699975. [Epub ahead of print]
    Motor unit discharge properties are modestly influenced by menstrual cycle-related fluctuations in sex hormone concentrations.
    MUSH Collaboration
      Concentrations of estradiol (E2) and progesterone (P4), the main female sex hormones, exhibit large fluctuations across the menstrual cycle. Due to their receptors throughout the central nervous system, both hormones have the potential to influence motor function by influencing ionotropic and metabotropic inputs to motor pools, which can be estimated through the neural codes extracted from motor unit discharge patterns. To address key methodological limitations in prior menstrual cycle research on motor output, we established the Motor Units and Sex Hormones (MUSH) collaboration. The objective of this multi-site investigation was to determine whether endogenous fluctuations in estradiol and progesterone influence human motor unit activity. We hypothesized that motor unit discharge rates and persistent inward current (PIC)-related contributions to discharge would be greatest during the late follicular phase, when estradiol concentrations were highest. Fifty females completed a comprehensive protocol involving menstrual cycle and ovulation tracking, serum hormone measurement, and high-density surface electromyographic recordings during isometric contractions to quantify motor unit activity in the early follicular, late follicular, and mid luteal phases. After exclusion of 10 females with either atypical hormone concentration profiles or insufficient motor unit yield, 40 remained in the final analysis. There were significant changes in several motor unit discharge variables between menstrual cycle phases and significant associations with hormone concentrations. Increased estradiol was associated with higher peak discharge rates and ascending discharge rate nonlinearity, while increased progesterone was associated with higher peak discharge rates, more discharge rate hysteresis and ascending discharge rate nonlinearity. Despite reaching statistical significance, the magnitudes of these effects (i.e., effect sizes) were small. Overall, these findings indicate that fluctuations in sex hormones influence motor unit behavior, but the effects are subtle, highlighting the need for well-powered and methodologically rigorous menstrual cycle research.
    KEY POINTS: There are small but detectable differences in motor unit discharge rates between menstrual cycle phases, which are predicted by within-participant fluctuations in estradiol and progesterone.Discharge rate patterns that provide estimates of neuromodulatory and inhibitory input suggest that estradiol and progesterone can influence spinal cord circuitry differently than has previously been documented in the brain, highlighting an understudied aspect of female neurophysiology.Variability in menstrual cycles and associate hormones makes large-scale, rigorous studies especially valuable in female neuromuscular research.
    DOI:  https://doi.org/10.64898/2026.01.16.699975
  10. Basic Clin Pharmacol Toxicol. 2026 Mar;138(3): e70201
    Sex Hormones Differentially Modulate Ochratoxin A-Induced Nephrotoxicity in Female Rats.
    Firdes Mor Savas, Mehmet Akif Kılıç, Ozlem Ozmen.
      Ochratoxin A (OTA) is a nephrotoxic mycotoxin associated with renal tumour development, particularly in male rats. However, the influence of sex hormones on OTA toxicity in females remains unclear. This study investigated the roles of oestrogen and testosterone in modulating OTA nephrotoxicity in female Wistar rats. Four-month-old females (~220 g) were divided into four groups: intact (F-OTA), ovariectomized (F-OVA-OTA), testosterone-supplemented (F-OTA-Test) and antitestosterone-treated (F-OTA-Antitest). Animals received OTA (40 μg/rat/day, feed) for 9 or 24 weeks. Hormonal manipulations involved subcutaneous testosterone (625 μg/rat) or intramuscular antitestosterone (6.25 μg/rat) for 9 weeks. Plasma OTA concentrations were higher in intact (12.43 μg/mL) and antitestosterone (13.46 μg/mL) rats than in ovariectomized (9.67 μg/mL) or testosterone-supplemented (9.76 μg/mL) groups (p < 0.05). Renal histopathology scores (0-3) showed most severe lesions in testosterone-treated rats (2.71 ± 0.75), followed by ovariectomized (2.14 ± 0.69), intact (1.60 ± 0.54) and antitestosterone (1.00 ± 0.00) animals (p < 0.001). These findings demonstrate that oestrogen enhances OTA accumulation, whereas testosterone exacerbates renal damage. Conversely, blocking testosterone confers histological protection, suggesting a protective effect of oestrogen. Collectively, the results reveal a hormonal antagonism, with oestrogen and testosterone exerting opposing influences on OTA toxicodynamics, carrying important implications for sex-specific mycotoxin risk assessment.
    Keywords:  female Wistar rats; histopathology; nephrotoxicity; ochratoxin A; oestrogen; testosterone; toxicodynamics
    DOI:  https://doi.org/10.1111/bcpt.70201
  11. PeerJ. 2026 ;14 e20646
    Sex differences in gut microbiota composition, function, and assembly in the plateau zokor (Eospalax baileyi).
    Lei Si, Rui Zhang, Jialong Guo, Haijing Wang, Jingyan Yan, Daoxin Liu.
       Background: Gut microbiota play a vital role in nutrient metabolism, immune regulation, and host homeostasis. However, the role of sex differences in shaping the gut microbiota of plateau zokors (Eospalax baileyi) remains unclear. The present study aims to explore how sex influences the composition, function, and assembly processes of the gut microbiota in plateau zokors.
    Methods: In this study, we performed Illumina 16S rRNA (V3-V4) sequencing on 15 gastrointestinal samples to assess sex-related differences in gut bacterial diversity, function, and community assembly.
    Results: No significant differences were observed in species richness or diversity between males and females; however, the gut microbial community structures differed significantly by sex (p < 0.01). At the phylum level, both sexes shared dominant phyla, including Firmicutes, Desulfobacterota, and Bacteroidota. Across both the phylum and genus levels, males and females shared the same dominant taxa, yet their relative abundances exhibited clear sex-specific differences. PICRUSt-based functional prediction indicated that the gut microbiota were mainly associated with energy metabolism, DNA repair, and cellular defense. Significant sex-related differences were detected in metabolic functions (p < 0.05), with males showing higher carbohydrate metabolism (p < 0.05), while females exhibited stronger xenobiotic biodegradation and metabolism (p < 0.05). Neutral community model (NCM) analysis showed that males (Nm = 228.21) had higher Nm values than females (Nm = 213.44), indicating greater microbial dispersal among males. Standardized neutrality score (NST) values (<0.5) indicated that deterministic processes predominantly governed community assembly in both sexes, with males exhibiting significantly lower values than females (p < 0.001). iCAMP analysis further revealed that drift and dispersal limitation were the primary assembly processes, with significant sex-related differences (p < 0.001).
    Conclusion: Sex differences markedly influence gut microbial structure, functions, and assembly processes in plateau zokors, offering new insights into the adaptive evolution of this species in cold, hypoxic environments.
    Keywords:  16S rRNA; Assembly processes; Functional prediction; Gut microbiota; Plateau zokor
    DOI:  https://doi.org/10.7717/peerj.20646
  12. Curr Opin Obstet Gynecol. 2026 Feb 02.
    A review of estrogens used in menopausal hormone therapy.
    Amythis Soltani, Amy J Voedisch.
       PURPOSE OF REVIEW: To provide an overview of endogenous and therapeutic estrogens, their receptor biology, clinical applications, and evolving safety considerations, with emphasis on how estrogen type, timing, and route of administration influence outcomes in menopausal hormone therapy (MHT).
    RECENT FINDINGS: Emerging research shows that estrogen receptor (ER)α, ERβ, and G protein-coupled estrogen receptor mediate distinct and sometimes opposing physiological effects. Updated analyses support the timing hypothesis, showing that starting MHT closer to menopause may yield cardiovascular and neurological benefits not observed with later initiation. Comparative studies demonstrate that estradiol has a more favorable thrombotic and metabolic profile than conjugated equine estrogens. Newer agents such as estetrol provide selective ERα activation with reduced hepatic stimulation and promising effects on vasomotor symptoms, bone turnover, and metabolic markers. Estriol has gained attention for its safety and effectiveness in treating genitourinary syndrome of menopause.
    SUMMARY: Estrogen therapy reflects a nuanced approach informed by receptor selectivity, pharmacologic diversity, and timing of initiation. Estradiol-based and transdermal formulations remain preferred for systemic therapy, while low-dose vaginal estrogen is first line for urogenital symptoms. Novel estrogens and deeper mechanistic insights continue to refine therapeutic options, supporting more targeted and safer use of estrogen across the menopausal transition.
    Keywords:  estrogen; hormone replacement therapy; hormones; menopausal hormone therapy; menopause
    DOI:  https://doi.org/10.1097/GCO.0000000000001090
  13. Am J Physiol Lung Cell Mol Physiol. 2026 Feb 05.
    Sex Chromosomes and Gonadal Sex Interactions in Airway and Immune Responses to Allergen Challenge.
    Carolyn Damilola Ekpruke, Dustin Rousselle, Rachel Alford, Omar Alejandro Borges-Sosa, Maksat Babayev, Shikha Sharma, Lyidia Dinwiddie, Erik Parker, Sarah Bradley, Matthew Louis Retzner, Patricia Silveyra.
      Asthma is a chronic respiratory condition influenced by genetic, environmental, and sex-related factors. Women experience greater asthma severity, airway hyperresponsiveness (AHR), and inflammation than men, likely due to sex-linked genetic and hormonal differences. However, the independent contributions of sex chromosomes and gonadal sex to these responses remain unclear. This study examines their roles in allergic airway responses using the Four Core Genotype (FCG) mouse model, which distinguishes between chromosomal and gonadal influences. We hypothesized that XX-mice and those with female gonads would exhibit heightened airway inflammation and immune activation in response to house dust mite (HDM) challenge. Using a controlled, moderate five-week HDM exposure paradigm that reliably induced allergic airway inflammation, we aimed to capture biologically relevant sex- and genotype-dependent variations rather than a maximal inflammatory phenotype. FCG mice (XXF, XXM, XYF, XYM) underwent 5 weeks of HDM exposure, followed by assessments of airway lung function and inflammation. Our results showed that HDM challenge differentially increased airway resistance and elastance in FCG mice, with specific contributions of sex chromosomes and gonadal sex. Histological analysis showed higher lung inflammation and goblet cell hyperplasia in challenged mice with female gonads than those with male gonads. Flow cytometry assessment revealed elevated eosinophils in XXF mice. Combined, our findings show that both sex chromosomes and gonadal sex influence airway inflammation and immune responses to allergen challenge, with mice bearing XX chromosomes and female gonads exhibiting greater susceptibility.
    Keywords:  Allergic Airway Inflammation; Four Core Genotype (FCG) model; Gonadal Hormones; Immune Cell Profiling; Sex Chromosomes
    DOI:  https://doi.org/10.1152/ajplung.00210.2025
  14. Front Immunol. 2025 ;16 1746620
    From gut dysbiosis to decidual hostility: the immuno-metabolic crosstalk driving recurrent pregnancy loss.
    Yimin Shi, Xiufeng Tang.
      Recurrent pregnancy loss (RPL), particularly its unexplained form (URPL), represents a formidable challenge in reproductive medicine. Although traditionally attributed to local immune imbalances at the maternal-fetal interface, this perspective may not fully account for the condition's upstream etiological drivers and recurrent nature. This review transcends this limitation by proposing and systematically substantiating an integrative 'gut-systemic-decidual' model of immunometabolic dysregulation. We posit that a key pathological cascade in many URPL cases may originate with distal gut dysbiosis, which, through imbalanced metabolite profiles and the leakage of inflammatory molecules such as lipopolysaccharide (LPS), triggers systemic 'metabolic endotoxemia' and fundamentally reprograms the metabolic state of circulating immune cells. This systemic 'first hit' is compounded when these 'pre-sensitized' cells migrate to an equally metabolically stressed and 'hostile' decidual microenvironment-a 'second hit' characterized by hypoxia and high lactate. This culminates in the functional collapse of the core sentinels of maternal-fetal tolerance, namely regulatory T (Treg) and decidual natural killer (dNK) cells, due to profound metabolic misprogramming. Ultimately, this integrated model elevates the etiological understanding of URPL from a 'local conflict' to that of a 'systemic disease,' paving the way for the development of dynamic warning systems that integrate multi-omics data and for the design of multi-level precision intervention strategies targeting patient stratification and preventive approaches for the gut, systemic metabolism, and the local microenvironment.
    Keywords:  decidual NK cells; decidual microenvironment; gut dysbiosis; immunometabolism; metabolic reprogramming; recurrent pregnancy loss; regulatory T cells
    DOI:  https://doi.org/10.3389/fimmu.2025.1746620
  15. Oncogene. 2026 Feb 06.
    Correction: Lysine methyltransferase SMYD2 enhances androgen receptor signaling to modulate CRPC cell resistance to enzalutamide.
    Junhong Li, Zhe Hong, Junyu Zhang, Shengfeng Zheng, Fangning Wan, Zheng Liu, Bo Dai.
      
    DOI:  https://doi.org/10.1038/s41388-026-03690-3
  16. Hum Reprod. 2026 Feb 03. pii: deaf252. [Epub ahead of print]
    Contribution of endometrial microbiome to inflammation-mediated infertility in women undergoing ART.
    F Giangrazi, J A Sugrue, V M Sularea, A A I Brugman, M Horan, M Wingfield, D A Crosby, L E Glover, C O'Farrelly.
       STUDY QUESTION: Is the endometrial microbiome altered in women who fail to get pregnant after ART and do microbial-derived metabolites influence endometrial cellular mechanisms important for embryo implantation?
    SUMMARY ANSWER: The endometrial microbiome in women who fail to get pregnant after ART is more diverse and has fewer lactobacilli species than the endometrial microbiomes of women who become pregnant; the short-chain fatty acid butyrate, a common metabolite found in the presence of increased microbial diversity, diminishes endometrial epithelial barrier function and increases the expression of inflammatory markers.
    WHAT IS KNOWN ALREADY: Shifts in the endometrial microbial community structure have been linked to fertility and pregnancy complications although the underlying mechanisms are poorly understood. Microbial metabolites at other mucosal surfaces, such as the gut, act as important modulators of immune and barrier function, particularly in epithelial cells. Effects of changes in local bacterial microbial populations on fertility, and how their metabolites might influence endometrial cell function have not been explored.
    STUDY DESIGN, SIZE, DURATION: In this prospective longitudinal study of ART outcomes, 29 nulliparous women with unexplained infertility were recruited between October 2016 and February 2018. Endometrial tissue samples were taken for microbiome analysis and endometrial transcriptomics prior to ART. For primary cell culture studies, endometrial biopsies were obtained from fertile women of reproductive age undergoing laparoscopic surgical investigation between February 2021 and September 2023. In vitro models of implantation were established using endometrial cell lines and primary endometrial stromal cells.
    PARTCIPANTS/MATERIALS, SETTING, METHODS: Microbiome 16S sequencing analysis was performed on bacterial DNA isolated from endometrial biopsies and correlated with receptivity markers. Endometrial RNA sequencing data from women undergoing ART were used to analyse differential gene expression of receptivity and decidualization markers in women who had a positive or negative ART cycle outcome. In vitro models, using both established endometrial cell lines and primary human endometrial epithelial cells and stromal cells, were developed to investigate the effects of microbial-derived metabolites. An in vitro model of peri-implantation was used to test the effect of butyrate on endometrial epithelial receptivity and stromal cell decidualization.
    MAIN RESULTS AND THE ROLE OF CHANCE: Endometrial microbiome 16S sequencing revealed a lower abundance of Lactobacillus spp. and significantly higher abundance of pathogenic species such as Prevotella spp. and Corynebacterium spp. in women who did not become pregnant after ART. Endometrial microbiota from women who had positive ART outcomes showed significantly lower diversity indices. Intriguingly, analysis of endometrial RNA sequencing data from women with unexplained infertility undergoing ART showed that negative ART outcomes were associated with higher levels of some receptivity and decidualization markers in their endometrial tissue. Butyrate, but not lactate or acetate, also increased some markers of epithelial receptivity and stromal decidualization. Butyrate exposure also activated defence mechanisms in cultured endometrial epithelial cells by inducing expression of antimicrobial peptide(s) and inflammation markers, as well as impairing the barrier integrity of endometrial epithelial cell monolayers.
    LARGE SCALE DATA: The RNA-seq data used for the study can be found in GEO database, GEO ID GSE144895. The data for the 16S sequencing can be accessed in SRA BioProject number PRJNA1338067.
    LIMITATIONS, REASONS FOR CAUTION: Limitations of our study include the cohort size and technical challenges that precluded absolute butyrate measurement in endometrial tissue biopsies. Biopsy collection from women undergoing gynaecological investigation varied in menstrual cycle staging and fertility diagnoses, which may contribute to the variability between responses obtained from in vitro stimulations. The transferred embryos were not genetically tested, but were all of good or top quality.
    WIDER IMPLICATIONS OF THE FINDINGS: Our findings indicate that the endometrial microbiome is altered in women who fail to become pregnant after ART, and that the microbial-derived metabolite butyrate can induce inflammation and impair endometrial epithelial barrier function and drive increased gene expression levels of markers for epithelial receptivity and stromal decidualization in in vitro models of peri-implantation. Endometrial microbial dysbiosis and higher expression of receptivity markers were found in women who failed to establish pregnancy post-ART. Negative ART outcomes in this cohort were found to correlate with the presence of a wider, more diverse microbial community that includes Prevotella spp., which is among the butyrate-producing bacteria. Further investigation of the microbial metabolome in healthy endometrium would help clarify the physiological role of butyrate and other bacterial metabolites in endometrial function.
    STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the Grant for Fertility Innovation from Merck KGaA, grant award number 15692. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
    TRIAL REGISTRATION NUMBER: N/A.
    Keywords:  16S-sequencing; assisted reproduction; endometrial epithelial cells; endometrial receptivity; endometrium; female infertility; inflammation; microbiome; unexplained infertility
    DOI:  https://doi.org/10.1093/humrep/deaf252
  17. Biol Sex Differ. 2026 Feb 02. 17(1): 17
    Sex-specific gonadal transcriptome during early development of Siberian sturgeon.
    André Lasalle Gerla, Germán Benech-Correa, Christophe Klopp, Denise Vizziano-Cantonnet.
       BACKGROUND: Sex determination and differentiation are complex processes shaped by a wide variety of molecular factors. In contrast to teleost species, many aspects of these processes remain poorly understood in basal non-teleost fishes such as the Siberian sturgeon (Acipenser baerii). Genetic sexing of this important aquaculture species now enables studies of undifferentiated males and females to identify factors involved in early sexual differentiation.
    METHODS: Twelve undifferentiated Siberian sturgeon (six males, six females) were genetically sexed at 2.5 months of age. High-quality RNA was extracted from gonad samples, and transcriptomes were assembled using a reference dataset. Bioinformatic analyses were performed to identify sex-biased genes through differential expression analysis, Gene Ontology (GO) enriched terms, and classification of coding and non-coding sequences.
    RESULTS: Genes potentially associated with sex differentiation were identified in gonadal tissue. Female-biased genes included classical estrogens production genes (hsd17b1, cyp19a1, foxl2) and immediate early response genes known to react rapidly to estrogens (jun-b, c-fos, egr1), as well as genes not previously linked to estradiol (di-ras2, ier2, aanat). The enriched Gene Ontology results suggested that melatonin signaling and hypothalamic pathways may also contribute to female differentiation. In males, the well-known factor tbx1 was upregulated along with novel candidates (plin1, nrxn3, chs2, mmp9). No sex-biased genes related to androgen production were identified.
    CONCLUSION: By 2.5 months of age, sex-specific gonadal differences are already apparent in Siberian sturgeon. This study highlights the estrogen response pathway, including immediate early response genes described here for the first time in the context of fish gonadal differentiation. At the same time, an estrogen-independent ovarian pathway cannot be ruled out. Male differentiation appears to involve tbx1 together with new candidates for testis regulation in the absence of sex-biased androgen-producing enzymes. These novel genes expressed near the onset of sex differentiation merit further investigation.
    Keywords:  Differential gene expression; Gonadal development; Gonadal transcriptome; Sex differentiation; Siberian sturgeon
    DOI:  https://doi.org/10.1186/s13293-025-00810-8
  18. Sci Technol Adv Mater. 2026 ;27(1): 2610875
    Distinct macrophage uptake of engineered and biological particles driven by host age and sex.
    Riki Toita, Yuki Shimizu, Jeong-Hun Kang.
      Understanding how nano- and microparticles interact with biological systems is essential for advancing the biomedical applications of engineered materials. These interactions are governed not only by the physicochemical properties of the particles - such as size, shape, and surface chemistry - but also by host-specific physiological factors. However, how intrinsic host factors, particularly age and biological sex, affect interactions between immune cells and particles remains poorly understood. In this study, we systematically investigated how these intrinsic host variables influence the cellular uptake of polymeric particles by primary macrophages. Using a library of particles with controlled sizes (25, 250, and 3000 nm) and surface chemistries (unmodified, amine-, and carboxyl-functionalized), as well as with biological particles (bacteria and yeast), we compared uptake efficiencies in macrophages derived from male and female mice of various ages. We observed significant age- and sex-dependent differences in particle internalization. Transcriptomic profiling revealed differentially expressed genes related to receptor-mediated endocytosis and actin cytoskeleton remodeling, suggesting that molecular mechanisms underly these variations. Additionally, protein coronas were formed by incubating polymeric particles with autologous serum, revealing sex-dependent differences in corona composition and resulting macrophage recognition. Our findings highlight the critical interplay between engineered-material properties and host biological variability. Accordingly, this work provides key insights for the rational design of nanomaterials tailored to perform consistently across heterogeneous biological populations, thereby advancing the development of personalized nanomedicine and immunomodulatory materials.
    Keywords:  Nanomedicines; RNA-seq; aging; biological sex; macrophages; uptake
    DOI:  https://doi.org/10.1080/14686996.2025.2610875
  19. Front Immunol. 2025 ;16 1733950
    The interactions between autophagy and immune in the liver-adipose-ovary circuit of polycystic ovary syndrome.
    Guofeng Nie, Muxuan Liu, Luxu Yang, Chanyu Li, Chenzhao Qu, Jing Wang, Juanjuan Mei, Yanlin Wang, Lei Han, Xinwei Zhang, Quanmin Wang.
      Polycystic ovary syndrome (PCOS) is a common reproductive, endocrine, and metabolic disorder in women of reproductive age, characterized by hyperandrogenemia, insulin resistance, and ovulatory dysfunction. Autophagy, a key cellular homeostasis mechanism, closely interacts with immune-inflammatory responses to drive PCOS pathogenesis. This review highlights the "liver-adipose-ovary circuit"-a pathological network where the liver, adipose tissue, and ovaries crosstalk via autophagy dysregulation, chronic low-grade inflammation, and metabolic disturbances. Abnormal autophagy in adipose tissue induces insulin resistance and inflammatory cytokine release; hepatic autophagy impairment exacerbates non-alcoholic fatty liver disease (NAFLD) and hyperandrogenemia; ovarian autophagy dysfunction disrupts folliculogenesis. These organ-specific abnormalities form a self-reinforcing cycle that amplifies PCOS phenotypes. Clinical therapies targeting this circuit (e.g., quercetin, metformin) show promise by regulating autophagy, improving insulin sensitivity, and restoring reproductive-metabolic balance. Future research should clarify inter-organ molecular mediators and validate autophagy-targeted strategies to advance personalized PCOS treatment.
    Keywords:  adipose; autophagy; inflammatory; liver; polycystic ovary syndrome
    DOI:  https://doi.org/10.3389/fimmu.2025.1733950
  20. Res Sq. 2026 Jan 13. pii: rs.3.rs-8368158. [Epub ahead of print]
    The Biosocial Microbiome: Gender Identity, Geography, and Mucosal Microbial Phenotypes.
    Vanessa Van Doren, S Smith, Cassie Grimsley-Ackerley, Jadah Keith, Robert Arthur, Henry Claussen, Phillip Murray, Vin Tangpricha, Yijuan Hu, Chang Su, Mengyu He, Colleen Kelley.
      Background Transgender women (TGW) experience unique hormonal contexts and high HIV incidence, yet the mucosal microbiome among TGW remains understudied. Sex hormones and geography may shape microbial composition, but the relative contributions of gender identity, feminizing hormone therapy (FHT), and location to mucosal microbial phenotypes among key populations such as TGW are unknown. Methods We conducted a multi-site study of cisgender men who have sex with men (MSM) and TGW using FHT, both without HIV, in Atlanta, Georgia, USA (n = 58; 25 TGW, 33 MSM) and Bangkok, Thailand (n = 147; 97 TGW, 50 MSM), using cross-sectional sampling (n = 205). We also conducted longitudinal sampling in TGW (n = 21) pre/post FHT initiation. Rectal mucosal swabs were collected from all participants with optional neovaginal sampling in TGW. Microbiota composition was analyzed using 16S rRNA sequencing, and associations with gender identity, geography, and serum estradiol and testosterone concentrations were assessed using linear decomposition modeling (LDM)(1) and BOUTH analysis(2). Results Rectal microbiota differed significantly by both gender identity and geography via LDM and BOUTH analyses. TGW exhibited enrichment of estrogen-metabolizing taxa across sites, while MSM showed Prevotellaceae enrichment in Atlanta but not Bangkok. Alpha diversity varied by location but not gender identity. Neovaginal microbiota differed markedly from rectal composition, showing enrichment of skin- and gut-associated taxa (e.g., Prevotella, Peptostreptococcus, Porphyromonas ) and anaerobic taxa associated with HIV seroconversion. Longitudinal analysis revealed no significant rectal microbiota shifts after short-term FHT initiation, possibly reflecting subtherapeutic hormone exposure. Conclusions These findings underscore the need to consider gender identity as a complex biosocial phenotype in HIV prevention and highlight the potential role of mucosal microbiota in shaping HIV vulnerability in TGW.
    DOI:  https://doi.org/10.21203/rs.3.rs-8368158/v1
  21. Biol Sex Differ. 2026 Jan 30.
    The gut-heart axis in coronary artery disease: a scoping and narrative review of sex-based microbial and metabolic disparities.
    Caroline Chong-Nguyen, Rubén Fuentes Artiles, Thomas Pilgrim, Bahtiyar Yilmaz, Yvonne Döring.
       BACKGROUND: The gut microbiota significantly influences cardiovascular health by regulating host metabolism and generating bioactive compounds like trimethylamine-N-oxide (TMAO) and indoxyl sulfate (IS), both linked to coronary artery disease (CAD). Emerging research indicates sex-based differences in microbial composition and metabolite production, yet their impact on CAD pathophysiology remains unclear. This scoping review summarizes current findings on sex-specific microbial and metabolic differences in individuals with CAD.
    METHODS: A systematic search of PubMed and EMBASE was conducted through March 2025 for peer-reviewed studies comparing gut microbiota or metabolite profiles between male and female patients with CAD. Eligible studies used 16S rRNA sequencing, shotgun metagenomics, or metabolite profiling to analyze microbial communities and atherosclerosis-associated metabolites. Mechanistic links from genetics, epigenetics, and hormone-microbiota interactions were integrated to provide a more comprehensive understanding of how gut microbiota may contribute to sex differences in CAD.
    RESULTS: Eleven studies met the inclusion criteria for this review. Men with CAD exhibited increased relative abundances of taxa such as Prevotella, Clostridia_UCG_014, UCG_010, and other pro-inflammatory genera, whereas women microbiota was comparatively enriched in Barnesiella, Bifidobacteriales, and other potentially beneficial taxa. Parallel differences emerged in microbial metabolite profiles: men demonstrated elevated plasma levels of TMAO and IS, both associated with heightened cardiovascular risk and disease burden. Conversely, women with CAD had higher circulating levels of secondary bile acids and lower TMAO concentrations.
    CONCLUSION: Preliminary studies suggest sex-related differences in gut microbiota composition and metabolite profiles in CAD patients. Integrating mechanistic links from microbial metabolism, genetics, epigenetics, and hormones supports a potential role of the microbiota in sex-dependent disease pathways. Current evidence is limited and mostly observational; well-designed studies are needed to clarify mechanisms, clinical relevance of sex-specific microbiome signatures and specifically assess whether these sex-specific microbial and metabolic differences influence CAD progression and outcomes.
    Keywords:  Coronary artery disease; Gut microbiota; Indoxyl sulfate; Metabolites; Sex difference; Trimethyl-amine-N-oxide
    DOI:  https://doi.org/10.1186/s13293-026-00824-w
  22. Genome Biol. 2026 Feb 04. 27(1): 2
    Sex-specific nonlinear DNA methylation aging trajectories reveal biomarkers of cancer risk and inflammation.
    Robin Grolaux, Macsue Jacques, Bernadette Jones-Freeman, Steve Horvath, Andrew Teschendorff, Nir Eynon.
       BACKGROUND: Aging is a multi-modal process, leaving distinct molecular signatures across the epigenome. DNA methylation is among the most robust biomarkers of biological aging, yet most studies assume linear age relationships and analyze mixed-sex cohorts, overlooking known sex differences. Such approaches risk obscuring critical nonlinear transitions and sex-specific trajectories.
    RESULTS: We develop SNITCH, a computational framework to detect complex nonlinear methylation trajectories and disentangle shared from sex-divergent patterns. Applied to the array-derived whole-blood methylomes from 252 females and 246 males (ages 19-90 years), SNITCH reveals convergent and divergent epigenetic aging pathways independent of immune cell composition. Nonlinear trajectories are enriched for developmental transcription factor motifs, including NF1/CTF and REST, with known oncogenic roles. Importantly, a female-specific nonlinear cluster is prospectively associated with cancer onset and systemic inflammation in an independent cohort, nominating clinically relevant biomarkers. We replicate the analysis in an additional cohort and highlight consistent nonlinear trajectories.
    CONCLUSIONS: Our results uncover sex-specific, nonlinear aging programs that capture the dynamics of epigenetic change beyond linear models. These findings provide potential candidate biomarkers for early disease risk and advance understanding of how aging trajectories diverge between sexes.
    Keywords:  Aging; Biomarkers; Computational biology; DNA methylation; Epigenetic; Nonlinear; Sex differences
    DOI:  https://doi.org/10.1186/s13059-026-03952-z
  23. Cell Mol Neurobiol. 2026 Feb 05.
    Neuroglial Function and Hormonal Modulation in Neurodegenerative Diseases: The Influence of Sex Hormones.
    Maitha M Alhajeri, Yara Abukhaled, Rayyah R Alkhanjari, Wesam Bassiouni, Hana Al-Ali, Amna Baig, Sara H Sembaij, Fatima A Al Muhairi, Zakia Dimassi, Hamdan Hamdan, Khaled S Abd-Elrahman.
      Astrocytes, microglia, and oligodendrocytes, key neuroglial cell types, are essential for central nervous system (CNS) homeostasis, immune regulation, and neuronal support. In neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), glial dysfunction contributes to pathogenesis via chronic inflammation, synaptic disruption, oxidative stress, and impaired myelination. Growing evidence highlights the regulatory influence of sex hormones on glial function. These hormones modulate inflammatory tone, synaptic remodeling, and remyelination, potentially contributing to sex-based differences in disease incidence, progression, and treatment response. This review synthesizes current understanding of glial involvement in neurodegeneration and examines how gonadal hormones interact with astrocytes, microglia, and oligodendrocytes. By integrating glial biology with neuroendocrinology, we propose that hormone-glia interactions represent promising, personalized targets for sex-informed therapies in CNS disorders.
    Keywords:  Estrogen; Neurodegeneration; Neuroglia; Neuroinflammation; Sex hormones; Testosterone
    DOI:  https://doi.org/10.1007/s10571-026-01674-1
  24. Mol Hum Reprod. 2026 Feb 05. pii: gaag006. [Epub ahead of print]
    Aberrant Progesterone Receptor (PGR) expression is associated with Estrogen Receptor 1 (ESR1) expression in the endometrium from infertile women with endometriosis.
    Sohyeon Yun, Soo Lim Kim, Eunhee M Jeong, Da-Hye Kang, Keun Cheon Kim, Tae Hoon Kim, Steve L Young, Bruce A Lessey, Jung-Yoon Yoo, Jae-Wook Jeong.
      Estrogen receptor 1 (ESR1) and progesterone receptor (PGR) are essential regulators for endometrial receptivity and embryo implantation. Their expression is dysregulated in women with endometriosis-associated infertility. However, the relationship between ESR1 and PGR within the same endometrial cellular compartments has not been clearly defined. In this study, we examined ESR1 and PGR expression and their correlation in mid-secretory phase eutopic endometrium from fertile women without endometriosis (n = 9) and infertile women with endometriosis (n = 11) using immunohistochemistry and multiplex immunofluorescence. ESR1 levels were significantly reduced in endometrial stromal cells from infertile women with endometriosis compared to controls, and this attenuation of ESR1 was tightly associated with reduced PGR expression. In contrast, although epithelial PGR is normally downregulated in receptive mid-secretory phase endometrium, aberrant epithelial PGR overexpression was strongly correlated with epithelial ESR1 levels in infertile women with endometriosis. Multiplex immunofluorescence and AI-assisted single-cell quantitative analysis further confirmed a significant positive correlation between ESR1 and PGR in both stromal and epithelial compartments in the endometriosis group. These findings reveal compartment-specific dysregulation of ESR1 and PGR expression and identify aberrant ESR1-PGR co-expression as a potential molecular feature of a non-receptive eutopic endometrium in endometriosis-associated infertility, underscoring the importance of disrupted steroid hormone signaling in impaired implantation.
    Keywords:  Endometriosis; Estrogen Receptor 1 (ESR1); Infertility; Multiplex immunofluorescence; Progesterone Receptor (PGR)
    DOI:  https://doi.org/10.1093/molehr/gaag006
  25. Endocr Pract. 2026 Jan 30. pii: S1530-891X(26)00036-4. [Epub ahead of print]
    Testosterone Replacement Therapy in Prostate Cancer Survivors Treated with Radiation with and without Androgen Deprivation Therapy: A Retrospective Study and Narrative Review.
    Mohan Sonu Chandra, Chengzhi Wang, Thiago Gagliano-Jucá, Eshaan Gaikwad, Yili Valentine Shang, Karol M Pencina, Shalender Bhasin.
       OBJECTIVES: Testosterone replacement therapy (TRT) in prostate cancer survivors with hypogonadism remains controversial due to concerns that restoring testosterone may increase the risk of disease recurrence. We performed a cohort study of men with localized prostate cancer treated with radiotherapy with or without androgen deprivation therapy (ADT), who received TRT, and a narrative review of published studies evaluating TRT after radiotherapy.
    METHODS: Biochemical and clinical recurrence, patient-reported symptoms, PSA, testosterone, and hemoglobin were analyzed in this cohort and published studies.
    RESULTS: Among 33 men with pathology-confirmed prostate cancer treated with radiation without or with ADT, who received TRT (median age at TRT initiation, 75 [IQR 69.0-77.0] years), median testosterone increased from 66.0 (IQR 16.0-140.0) to 299.3 (IQR 152.5-569.0, p<0.001) ng/dL. PSA rose from 0.04 (IQR 0.02-0.17) to 0.17 ng/mL (IQR 0.04-0.44) (p=0.018). TRT was associated with improvements in fatigue, mood, and sexual symptoms; anemia was corrected in 9 of 21 (42.9%) patients with anemia. One patient (3%) developed metastatic disease 3 years after starting TRT. In narrative review of published case-reports, weighted mean biochemical recurrence rate was 3.3% during mean 42.6 months of follow-up.
    CONCLUSIONS: Our cohort study and narrative review found a low incidence of biochemical recurrence in prostate cancer survivors treated with radiation therapy with or without ADT. TRT was associated with correction of anemia and improvements in fatigue, energy, and sexual symptoms. These findings provide the ethical and scientific rationale for a randomized controlled trial to evaluate the safety and efficacy of TRT in this population.
    Keywords:  androgen deprivation therapy; hypogonadism; prostate cancer survivors; radiation treatment; testosterone treatment
    DOI:  https://doi.org/10.1016/j.eprac.2026.01.019
  26. Front Endocrinol (Lausanne). 2025 ;16 1769798
    Estrogenic control of germ cell differentiation in medaka: independence of early sex dimorphism from zygotic estrogen and receptor signaling.
    Yuta Sakai-Yamada, Taijun Myosho, Daichi Kayo, Shinji Kanda, Tohru Kobayashi.
       Background: Estrogen signaling is essential for ovarian differentiation in vertebrates, but its developmental onset and specific roles during early gonadogenesis remain unclear. In medaka (Oryzias latipes), the first morphological sex difference appears as a higher germ cell number in XX compared with XY embryos before hatching. Recently, we demonstrated that zygotically synthesized estrogen was dispensable for early germ cell sex difference but essential for subsequent oocyte meiotic progression and ovarian fate maintenance. Nevertheless, whether these phenomena depend on maternal estrogen or zygotic estrogen signaling mediated by nuclear estrogen receptors (nEsrs) is unknown.
    Objective: To clarify the receptor-level requirement of estrogen signaling, we generated esr1/2a/2b triple knockout (ΔnEsrs) medaka using CRISPR/Cas9 genome editing. By comparing these receptor-deficient mutants with our previous ligand-deficient (Δcyp19a1a/1b double knockout) model, we aimed to determine whether estrogen signaling is involved in the establishment of the early germ cell number difference or acts later to control meiotic progression and ovarian maintenance.
    Methods: We established ΔnEsrs medaka using CRISPR/Cas9 and analyzed gonadal histology, germ cell kinetics, and expression of steroidogenic enzyme genes, sex differentiation-related genes, and oocyte-specific expressed genes during early development.
    Results: ΔnEsrs mutants displayed normal early germ cell number and sex-specific differences at hatching (0 dph). At 10 dph, diplotene oocytes were markedly reduced, accompanied by significant downregulation of oocyte-specific genes, figa, 42sp50, as well as cyp19a1a and foxl2 mRNA. However, ΔnEsrs did not cause feedback regulation on other hypothalamus-pituitary-gonad (HPG) axis gene expression.
    Conclusion: Our results demonstrate that estrogen signaling, both at the ligand and receptor levels, is dispensable for establishing the early germ cell sex difference but essential for subsequent oocyte meiotic progression and ovarian fate maintenance. This establishes a two-step estrogenic control model, redefining the developmental timing of estrogen action during the early phase of gonadal differentiation in vertebrate reproduction.
    Keywords:  estrogen receptor; germ cell number; medaka; null; oogenesis; sex differentiation
    DOI:  https://doi.org/10.3389/fendo.2025.1769798
  27. J Appl Physiol (1985). 2026 Feb 05.
    Estrogen Receptor Alpha Determines Sex-Specific Cardiorespiratory and Autonomic Responses to Intermittent Hypoxia in Mice.
    Ella Aka, François Marcouiller, Vincent Joseph.
      Despite the evidence that responses to intermittent hypoxia (IH) vary between sexes, potentially underlying sex-specific comorbidities of sleep apnea, the roles that sex hormones play during exposure to IH in rodent models remain poorly defined. The Estradiol receptor ɑ (ERɑ), expressed in structures of the peripheral and central nervous system, contributes to autonomic regulations and control of arterial blood pressure, accordingly, we tested the hypothesis that ERα modulates respiratory and heart rate variability in male and female mice exposed to IH. We used adult wild-type (WT) and ERα knockout (ERαKO) mice of both sexes for whole-body plethysmography, arterial blood pressure and ECG recordings before and after 14 days of IH (6% O₂, 12 cycles/h, 12 h/day). Compared to males, WT females exhibited greater respiratory variability and higher apnea frequency before IH exposure. In females, ERα deletion increased body weight, and reduced post-sigh apnea frequency before IH exposure. In ANCOVA/GLM models, body weight was a significant negative covariate for post-sigh and spontaneous apneas before IH exposure, while sex and genotype effects were not significant after adjustment. IH exposure increased the mean and diastolic blood pressures only in WT males. IH also increased apneas frequency in WT females, an effect markedly reduced by ERɑ deletion. Similarly, heart rate variability increased in WT females following IH, reflecting enhanced parasympathetic modulation, an effect absent in ERαKO females and in WT or ERαKO males. We conclude that in female mice, deletion of ERα prevents IH-induced improvement of heart rate variability.
    Keywords:  Estradiol Receptor; Heart Rate Variability; Respiratory Control; Respiratory Variability; Sleep Apnea
    DOI:  https://doi.org/10.1152/japplphysiol.01146.2025
  28. Cancer Cell. 2026 Feb 05. pii: S1535-6108(26)00044-9. [Epub ahead of print]
    Male-biased Yap1-Cd276/B7-H3 axis for immune evasion in medulloblastoma.
    Nourhan Abdelfattah, Sivaraman Natarajan, Han Nhat Tran, Thomas Wong, Maryam Faisal, Jose Maldonado, Rachael McMinimy, Hannah Borland, Shu-Hsia Chen, Hong Zhao, Matthew Vasquez, Freddys F Rodriguez, Carston R Wagner, Fernando Camargo, James Olson, Joshy George, Kyuson Yun.
      Molecular mechanisms underlying sex-specific differences in cancer incidence and therapy responses are under intense investigation. Here, we report sex-biased functions of Yap1 in multiple cancer types in human and mouse. Through integrated multi-omics analyses, we demonstrate that Yap1 deletion significantly extends survival in male but not female Sonic Hedgehog (SHH) medulloblastomas (MB) models. While Yap1 is required to maintain stem-like cells in both sexes, Yap1 plays a more critical role in immune evasion in males. Mechanistically, YAP1 is essential for activating Cd276/B7-H3 expression to mediate CD8+ T cell suppression in males. Consistently, CD276 inhibition extends survival in male but not female SHH MB. Moreover, in vivo targets of YAP1 stratify survival in male but not female patients with medulloblastoma, glioblastoma, mesothelioma, and lung cancer. This study provides evidence for sex-biased functions of Yap1 and CD276 in MB immune suppression and highlights the importance of biological sex in cancer:immune interactions.
    Keywords:  CD276/ B7-H3; YAP1; brain tumor; cancer stem cells; immune evasion; immunotherapy; medulloblastoma; sex bias; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ccell.2026.01.005
  29. Hum Reprod Open. 2026 ;2026(1): hoag001
    Comprehensive 16S rRNA gene sequencing and meta-transcriptomic analyses of the female reproductive tract microbiota: two molecular profiles with different messages.
    Alberto Sola-Leyva, Inmaculada Pérez-Prieto, Analuce Canha-Gouveia, Eduardo Salas-Espejo, Nerea M Molina, Eva Vargas, Apostol Apostolov, Amruta D S Pathare, Sergio Vela-Moreno, Susana Ruiz-Durán, Bárbara Romero, Rocío Sánchez, José Antonio Castilla-Alcalá, Merli Saare, Ganesh Acharya, Andres Salumets, Signe Altmäe.
       STUDY QUESTION: Does the analysis of endometrial microbes provide the same information when using DNA or RNA sequencing-based techniques?
    SUMMARY ANSWER: DNA vs RNA-based microbial analysis techniques demonstrated significant microbial compositional differences and lack of transcriptionally active lactobacilli in the endometrium.
    WHAT IS KNOWN ALREADY: Our understanding of the endometrial microbiome is primarily based on DNA-based 16S rRNA gene profiling, but DNA detection does not imply the presence of living microbes. While this method is cost-effective and widely used, it has notable limitations, including the underestimation of microbial diversity, abundance, and functionality, as well as limited species-level resolution. While the microbiome reflects DNA-based characterization, the microbiota more precisely captures metabolically active communities. In this context, meta-transcriptomic analysis, an RNA-based approach, addresses these shortcomings by capturing functional transcripts that are actively expressed in living microbes.
    STUDY DESIGN SIZE DURATION: This cross-sectional study consisted of 49 reproductive-aged women (27-42 years old) who were receiving ART. By simultaneously analysing the microbial composition and gene expression within female reproductive tract samples, we sought to provide a more comprehensive understanding of the microbiota and functional potential of these samples.
    PARTICIPANTS/MATERIALS SETTING METHODS: Vaginal swabs, endometrial brushing, and endometrial biopsy samples were collected from 49 participants during the mid-secretory phase of their menstrual cycle, 6-9 days after the luteinizing hormone surge for parallel 16S rRNA gene sequencing and meta-transcriptome analyses. For DNA-based analysis, the 16S rRNA gene V4 region was sequenced. For RNA-based analysis, total RNA was extracted followed by ribosomal RNA depletion. Strand-specific total RNA sequencing libraries were prepared and sequenced. Taxonomy was assigned by using Kraken2 (v2.2.1), and Bracken (v2.7).
    MAIN RESULTS AND THE ROLE OF CHANCE: Our findings suggest that in low-microbial-biomass environments such as the endometrium, the correlation between 16S rRNA gene sequencing and meta-transcriptomics is relatively weak. This highlights the limitations of microbial analysis of low-microbial-biomass samples. Alternatively, microbial functions and genome activity may be tissue-specific and dependent on the host tissue environment. Moreover, RNA-based analysis provides higher resolution in detecting certain pathogens, even within the endometrium.
    LARGE SCALE DATA: The data presented in the study are deposited in the NCBI SRA Database, accession number PRJNA1247240.
    LIMITATIONS REASONS FOR CAUTION: High levels of host RNA and the low abundance of microbial reads in the endometrium complicate microbial identification. Our findings indicate that RNA-seq enables precise profiling of the vaginal microbiome and, in cases of dysbiosis, reveals higher pathogen activity than DNA-based approaches. However, the limited sample size restricts the generalization of these conclusions.
    WIDER IMPLICATIONS OF THE FINDINGS: Contrary to the general belief of the dominance of Lactobacillus in the human endometrium, our study suggests that the endometrial microenvironment may be harbouring DNA fragments and/or cells of lactobacilli originating from the lower reproductive tract. Our study results indicate a need to re-consider/re-analyse the endometrial microbiome in health and disease.
    STUDY FUNDING/COMPETING INTERESTS: This work was supported by the projects Endo-Map PID2021-127280OB-I00, ROSY CNS2022-135999, and ENDORE SAF2017-87526-R funded by MICIU/AEI/10.13039/501100011033 and by FEDER, EU. This work was also supported by the Estonian Research Council grants (PSG1082 and PRG1076), Swedish Research Council grant no. 2024-02530 and Novo Nordisk Foundation grant no. NNF24OC0092384. Additionally, A.S.L. and I.P.P. acknowledge Becas Fundación Ramón Areces para Estudios Postdoctorales-Convocatorias XXXV and XXXVI, para Ampliación de Estudios en el Extranjero en Ciencias de la Vida y de la Materia. A.S. is supported by Horizon Europe (NESTOR, grant no. 101120075) and the Ministry of Education and Research Centres of Excellence grant TK214 name of CoE. All the authors declare no conflict of interest.
    Keywords:  16S rRNA gene; dysbiosis; endometrial microbiome; meta-transcriptome; microbial activity; microbiota
    DOI:  https://doi.org/10.1093/hropen/hoag001
  30. Genome Biol Evol. 2026 Feb 04. pii: evag026. [Epub ahead of print]
    Evolutionary dynamics of dosage compensation and sex-biased gene expression in morabine grasshopper Vandiemenella viatica.
    Suvratha Jayaprasad, Holger Schielzeth, Octavio M Palacios-Giménez.
      Sex chromosome evolution and gene regulation are closely linked but remain understudied in many taxa. Young neo-sex chromosomes offer unique insights into these processes. We examine dosage compensation (DC) and sex-biased gene expression in Vandiemenella viatica grasshoppers by comparing the ancestral X chromosome in the P24X0 race with derived neo-sex chromosomes in the P24XY race. The P24XY neo-XY arose via X-autosome fusion: the XL arm represents the ancestral X and the XR arm a former autosome (chromosome 1 in P24X0) now part of the neo-X and homologous to the neo-Y. We first assess DC via male and female gene expression. In somatic tissues, male P24X0 X-linked and P24XY XL-linked genes are upregulated to match both female expression and autosomal levels, indicating near-complete DC. In testes, expression of X-linked and the XL-linked genes is reduced nearly fourfold reflecting absent DC and the presence of meiotic X chromosome inactivation. We then analyse sex-biased gene expression across tissues and chromosomes. Gonads show stronger sex-biased gene expression than somatic tissues. Female-biased genes are concentrated on the P24X0 X and P24XY XL, where male-biased genes are enriched on autosomes and the XR arm of the neo-X. Overall, the ancestral X in P24X0 and the XL arm of the P24XY neo-X are hypertranscribed, while the XR arm retains autosomal expression, male-biased enrichment, and lacks DC. These patterns show that DC is regulated at levels of chromosome arms and illustrate how chromosome structure, gene regulation, and reproduction interact, shedding light on sex chromosome evolution in V. viatica.
    Keywords:  Dosage compensation; Sex-biased gene expression; X-linked genes; transcriptional regulation
    DOI:  https://doi.org/10.1093/gbe/evag026
  31. Free Radic Res. 2026 Feb 07. 1-15
    Follicular Fluid Oxidative Stress and Antioxidant Defense in Relation to Maternal Age, Ovarian Reserve, and In Vitro Fertilization Outcomes.
    Oya Korkmaz, Seda Karabulut, Pelin Macit, Çağrı Çakıcı.
      Oxidative stress within the follicular microenvironment plays a critical role in oocyte quality and reproductive outcomes. This prospective study examines the association between follicular fluid redox status, maternal age, ovarian reserve, and clinical outcomes in women undergoing in vitro fertilization. Follicular fluid samples were obtained from women undergoing fresh embryo transfer cycles and analyzed for oxidative damage markers (malondialdehyde, nitric oxide, ischemia-modified albumin, sialic acid) and antioxidant parameters (superoxide dismutase, catalase, glutathione, and thiol-disulfide homeostasis). Participants were stratified according to maternal age (≤35 vs. >35 years), serum estradiol levels on the day of human chorionic gonadotropin trigger (≤90th vs. >90th percentile), and clinical pregnancy outcome. Anti-Müllerian hormone and follicle-stimulating hormone levels were recorded as indicators of ovarian reserve. Women aged >35 years exhibited significantly higher malondialdehyde and sialic acid levels, accompanied by reduced antioxidant enzyme activities. Cycles resulting in clinical pregnancy showed lower oxidative stress and higher antioxidant capacity compared with non-pregnant cycles. Malondialdehyde levels correlated positively with age and follicle-stimulating hormone, while antioxidant parameters correlated positively with anti-Müllerian hormone and pregnancy outcome. Receiver operating characteristic analysis demonstrated moderate discriminative ability of malondialdehyde, superoxide dismutase, catalase, and glutathione for clinical pregnancy. These findings indicate that age-related redox imbalance in follicular fluid is associated with diminished ovarian reserve and reduced in vitro fertilization success. Assessment of follicular fluid oxidative stress parameters may provide clinically relevant insights into female reproductive potential.
    Keywords:  Antioxidants; Follicular Fluid; In Vitro Fertilization; Ovarian Reserve; Oxidative Stress
    DOI:  https://doi.org/10.1080/10715762.2026.2629303
  32. PLoS Biol. 2026 Feb;24(2): e3003575
    Resource landscape shapes the composition and stability of the human vaginal microbiota.
    Tsukushi Kamiya, Mircea T Sofonea, Michael France, Nicolas Tessandier, Ignacio G Bravo, Carmen Lia Murall, Jacques Ravel, Samuel Alizon.
      The vaginal microbiota is associated with the health of women and newborns alike. Despite its comparatively simple composition relative to other human microbiota systems, the mechanisms underpinning the dynamics and stability of vaginal microbial communities remain elusive. A crucial, yet so far underexplored, aspect of vaginal microbiota ecology is the role played by nutritional resources. Glycogen and its derivatives, produced by vaginal epithelia, are accessible to all bacterial constituents of the microbiota. Concurrently, free sialic acid and fucose offer supplementary nutritional resources to bacterial strains capable of cleaving them from glycans, which are structurally integral to mucus. Notably, bacteria adept at sialic acid exploitation are often correlated with adverse clinical outcomes and are frequently implicated in bacterial vaginosis (BV). In this study, we introduce a novel mathematical model tailored to human vaginal microbiota dynamics to explore the interactions between bacteria and their respective nutritional landscape. Our resource-based model examines the impact of the relative availability of glycogen derivatives (accessible to all bacterial species) and sialic acid (exclusive to some BV-associated bacteria) on the composition of the vaginal microbiota. Our findings elucidate that the success of BV-associated bacteria is intricately linked to their exclusive access to specific nutritional resources. This private access fortifies communities dominated by BV-associated bacteria, rendering them resilient to compositional transitions. We empirically corroborate our model prediction with longitudinal clinical data on microbiota composition and previously unpublished metabolomic profiles obtained from a North American cohort. The insights gleaned from this study shed light on potential pathways for BV prevention and treatment.
    DOI:  https://doi.org/10.1371/journal.pbio.3003575
  33. mBio. 2026 Feb 05. e0364525
    Not all vaginal microbiomes are equal: functional context shapes immune landscapes.
    Amanda Williams, Amaury Maros, Michael T France, Jacques Ravel, Johanna B Holm.
      Taxonomic classification alone fails to capture the ecological and functional diversity of vaginal microbiomes, particularly those dominated by Gardnerella species. Using the expanded VIRGO2 gene catalog, we developed the vaginal inference of subspecies and typing algorithm (VISTA), a novel ortholog-based framework that defined metagenomic subspecies and 25 metagenomic community state types (mgCSTs), including six distinct Gardnerella-dominated profiles. The mgCSTs exhibit marked differences in species composition, functional gene content, transcriptional activity, and host immune responses. These findings reveal that Gardnerella predominance does not uniformly equate to dysbiosis and underscore the importance of functional context in shaping host-microbiome interactions. VISTA provides scalable classifiers and an interactive application to support mechanistic studies of vaginal microbiome function and its implications for reproductive health.IMPORTANCEThe vaginal microbiome plays a central role in reproductive and gynecologic health, yet its functional diversity and ecological organization remain poorly understood. Traditional 16S rRNA approaches provide only a partial view of this complexity, overlooking the strain-level variation that often determines microbial behavior and host outcomes. By applying metagenomic sequencing and scalable computational modeling, we developed the vaginal inference of subspecies and typing algorithm, a framework that defines gene-based subspecies and community state types across diverse populations. These classifications reveal new insights into the genomic and ecological foundations of vaginal community structure and offer a standardized resource for comparative and translational microbiome research. This work establishes the foundation for functionally informed diagnostics and precision interventions targeting women's reproductive health.
    Keywords:  Lactobacillus; anaerobes; bioinformatics; community structure; gene expression; immunology; lactate dehydrogenase; metagenomic; metatranscriptomics; microbial communities; microbiota; vagina
    DOI:  https://doi.org/10.1128/mbio.03645-25
  34. Front Immunol. 2025 ;16 1679493
    Metabolic reprogramming tailors T cell immunity in sepsis.
    Di Xian, Feng Chen, Bing Liu, Lei Wang.
      Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, characterized by persistently high morbidity and mortality. Current treatment strategies have limitations, particularly the persistence of an immunosuppressed state. Recent studies have revealed that sepsis not only causes immune system dysregulation but also leads to metabolic disturbances, specifically metabolic reprogramming in T cells-a field still in its early stages. This review systematically explores the mechanisms of T-cell metabolic reprogramming in sepsis, including enhanced glycolysis, mitochondrial dysfunction, and dysregulated amino acid metabolism. It further analyzes how these alterations, mediated by signaling pathways such as HIF-1α, mTOR, and AMPK, as well as key metabolic enzymes, exacerbate T-cell exhaustion and immunosuppression. The article elaborates on the role of metabolic reprogramming in T-cell dysfunction and susceptibility to secondary infections, and summarizes potential therapeutic strategies targeting metabolic pathways-such as IL-7 therapy and IDO1 inhibitors-for restoring T-cell function, offering new directions for sepsis immunotherapy.
    Keywords:  T-cell immunity; immunosuppression; metabolic reprogramming; sepsis; therapeutic strategies
    DOI:  https://doi.org/10.3389/fimmu.2025.1679493
  35. Aging Cell. 2026 Feb;25(2): e70392
    Sex Differences in Associations Between Adversity and Biological Ageing.
    Julian Mutz, Luca Di Benedetto, Thole H Hoppen, Nexhmedin Morina, Monica Aas.
      Adverse events across the life course have been linked to older biological ageing profiles. Whether these associations differ between males and females, and whether such differences depend on adversity occurring in childhood, adulthood or both periods, remains unclear. In 153,557 UK Biobank participants aged 40-69 years, we assessed associations of childhood and/or adulthood adversity with metabolomic ageing, frailty, telomere length and grip strength. Sex differences were evaluated using stratified analyses and sex-by-adversity interaction tests. Exposure to adversity in childhood and/or adulthood was reported by 64.6% of males and 69.6% of females. Childhood adversity was associated with multiple ageing markers primarily in females, including a metabolite-predicted age exceeding chronological age, greater frailty, shorter telomeres and weaker grip strength. Adulthood adversity was more strongly associated with certain ageing markers in males, particularly greater frailty and weaker grip strength. This divergence in sex-specific associations between childhood and adulthood exposure was consistent across several markers, with statistically significant sex-by-adversity interactions for frailty and grip strength. In this large, population-based sample, the timing of adversity, distinguishing childhood from adulthood, shaped whether females or males showed stronger associations with biological ageing markers. These findings suggest that sex differences in biological ageing profiles may partly reflect distinct sensitive periods of vulnerability, highlighting the importance of considering both sex and timing of exposure to adversity when examining links between adversity and biological ageing.
    DOI:  https://doi.org/10.1111/acel.70392
  36. Front Nutr. 2025 ;12 1709581
    Multi-omics elucidation of Lactiplantibacillus plantarum NKK20 in preventing PCOS via the gut-ovary axis: SCFAs-mediated microbiota-metabolite-immune crosstalk.
    Hao Xu, Xinyu Liu, Wen Sun, Xueyun Dong, Xuehui Liu, Yunhan Xie, Jiayuan He, Asmaa Ali, Min Chen, Liang Wu, Jie Ma, Keke Shao.
       Purpose: Polycystic ovary syndrome (PCOS) is a clinically prevalent endocrine and metabolic disorder characterized by gut microbial disturbances and chronic low-grade inflammatory responses.
    Methods: This study explores the therapeutic potential and mechanistic insights of Lactiplantibacillus plantarum NKK20 (LP) in a PCOS murine model established through high-fat diet (HFD) and letrozole co-induction. By integrating multi-omics profiling (16S rRNA sequencing and untargeted metabolomics) with histopathological evaluation, we systematically assessed LP-mediated modulations of gut microbiota composition, metabolic signatures, ovarian function, and intestinal barrier integrity.
    Results: The results demonstrated that LP administration effectively counteracted metabolic dysregulation in PCOS mice, mitigating body weight gain, ameliorating lipid abnormalities (reduced total cholesterol, triglycerides, and LDL-C alongside elevated HDL-C), and lowering fasting glucose levels. Hormonally, LP suppressed hyperandrogenism, as evidenced by decreased testosterone, while rebalancing inflammatory mediators through IL-10 upregulation and concomitant reduction of TNF-α, IL-6, IL-1β, and MCP-1. Ovarian histomorphology revealed attenuated follicular cysts and enhanced luteinization. Critically, LP restored intestinal homeostasis by (i) augmenting short-chain fatty acid (SCFA) production-particularly butyrate-(ii) fortifying the gut barrier via increased ZO-1 and occludin expression, and (iii) diminishing circulating endotoxin. Microbial sequencing identified enrichment of Bacteroidetes and Muribaculum following LP treatment. Serum metabolomics further uncovered LP-induced normalization of steroid hormone biosynthesis and glycerophospholipid metabolism, coinciding with elevated anti-inflammatory mediators such as 6a-prostaglandin I1.
    Conclusion: Collectively, these findings delineate a novel preventive axis through which LP inhibits PCOS progression - namely, via coordinated "gut microbiota-metabolite-ovarian" crosstalk involving SCFA-mediated barrier restoration, microbial ecology stabilization, and suppression of ovarian inflammatory onset. This work advances the translational rationale for probiotic-based strategies in PCOS prevention.
    Keywords:  Lactiplantibacillus plantarum NKK20; gut microbiota; gut-ovary axis; metabolomics; polycystic ovary syndrome; short-chain fatty acids
    DOI:  https://doi.org/10.3389/fnut.2025.1709581
  37. Mol Biol Rep. 2026 Feb 03. 53(1): 351
    Differential gene expression profiling of ectopic endometrium reveals key molecular pathways in endometriosis pathogenesis.
    Gunjan Rai, Ashish Ashish, Sangeeta Rai, Shivani Mishra, Surbhi Singh, Royana Singh.
       BACKGROUND: Endometriosis is a chronic, estrogen-dependent inflammatory disease characterized by the presence of endometrial-like tissue outside the uterine cavity and is associated with pain, infertility, and impaired quality of life. Although its etiology is multifactorial, the molecular mechanisms underlying lesion establishment and persistence remain incompletely understood.
    METHODS: This study investigated differential gene expression in ectopic endometrial tissues obtained from women with surgically and histologically confirmed endometriosis, compared with eutopic endometrium from healthy fertile controls. Targeted quantitative real-time PCR was performed to evaluate genes involved in epigenetic regulation, inflammation, angiogenesis, extracellular matrix remodeling, developmental pathways, and hormone signaling. Bioinformatics analyses, including Gene Ontology (GO) enrichment and protein-protein interaction (PPI) network analysis, were applied to elucidate functional pathways and gene interaction networks. Clinical and biochemical parameters were correlated with disease severity classified according to the revised American Society for Reproductive Medicine (rASRM) staging system.
    RESULTS: A total of 35 differentially expressed genes were identified, comprising 18 upregulated and 17 downregulated genes. Upregulated genes were predominantly associated with DNA methylation, inflammatory signaling, and angiogenesis, including DNMT1, DNMT3A, VEGFA, IL6, TNF-α, and MMP9, whereas downregulated genes included developmental and hormone-responsive regulators such as HOXA10, HOXA11, ESR1, PGR, and FOXO1. GO analysis revealed significant enrichment of epigenetic modification, immune response, and extracellular matrix organization among upregulated genes, while downregulated genes were enriched in developmental and transcriptional regulatory processes. PPI network analysis identified key hub genes within interconnected functional modules. Clinical and biochemical parameters, including serum CA-125 and CRP, increased progressively with rASRM stage.
    CONCLUSION: This study highlights coordinated dysregulation of epigenetic, inflammatory, angiogenic, and hormonal pathways in ectopic endometrial tissues, contributing to the molecular pathogenesis of endometriosis. While these findings provide insight into disease-associated molecular networks, further validation in larger and independent cohorts is required to clarify their biological and clinical relevance.
    Keywords:  DNA methylation; Endometriosis; Epigenetic regulation; Gene expression; HOX genes; Inflammation
    DOI:  https://doi.org/10.1007/s11033-026-11521-7
  38. Rhinology. 2026 Feb 01. 64(1): 1
    Sex-specific differences in chronic rhinosinusitis with nasal polyps: toward more personalized management.
    S Toppila-Salmi.
      Chronic rhinosinusitis with nasal polyps (CRSwNP) is increasingly recognized as a biologically heterogeneous disorder, in which patient-specific factors strongly influence outcomes. Among these, sex-related differences have been observed clinically, yet their underlying pathological basis and impact on postoperative recurrence remain incompletely understood.
    DOI:  https://doi.org/10.4193/Rhin26.901
  39. J Nutr Biochem. 2026 Feb 04. pii: S0955-2863(26)00028-8. [Epub ahead of print] 110286
    Maternal fructose consumption differentially programs the allergic airway response in male and female mouse offspring.
    Amanda Santos Cavalcante, Rodrigo Rodrigues E Lacerda, Carolina Vieira Campos, Vinicius Cooper Capetini, Yuri Richard Silva da Conceição, Silvana Bordin, Yanira Riffo-Vasquez, Gabriel Forato Anhê.
      Epidemiological studies describe a positive correlation between sugar consumption during pregnancy and the risk for atopic respiratory diseases in the progeny. In the present study we developed an experimental model to test whether the offspring born to and/or breastfed by mice exposed to liquid fructose would manifest changes in the allergic airway disease induced by sensitization and challenge with ovalbumin (OVA). Male mice born to mothers consuming fructose during pregnancy and/or lactation exhibited exacerbated infiltration of eosinophils and lymphocytes in the bronchoalveolar lavage (BAL) after challenge with OVA. Such changes were not detected in the female progeny. On the other hand, the OVA-challenged female progeny born to and breastfed by mothers consuming fructose exhibited higher concentrations of IL-4, IL-5 and TGF-β1 in the BAL and IgE in serum. Additional characteristics that were specifically programmed in the male progeny born to mothers exposed to fructose during pregnancy and lactation comprised increased BAL levels of IL-10, eosinophil infiltration in the lung parenchyma, lung collagen deposition and goblet cell numbers and ccl11, muc5b and receptor for advanced glycation endproducts expression in the lung. Altogether, our experimental approach reveals a previously undescribed causal relationship between maternal fructose consumption and changes in the allergic response in the offspring exposed to the OVA model. Such changes are sex-specific and while the female progeny exhibits higher IL-4, IL-5, TGF-β1 and IgE levels upon challenge with OVA, only the male offspring manifested exacerbated hallmarks of severe disease, including cellular infiltration, goblet cell hyperplasia, and collagen deposition.
    Keywords:  allergic airway disease; fructose;pregnancy; lactation; offspring
    DOI:  https://doi.org/10.1016/j.jnutbio.2026.110286
  40. Redox Rep. 2026 Dec;31(1): 2622747
    The estrogen-progestogen-oxidative stress network in uterine fibroids: mechanistic insights and therapeutic opportunities.
    Siyu Wang, Wanhui You, Danni Ding, Fangyuan Liu, Fengjuan Han, Liping Tang.
      Uterine fibroids are benign tumors with high incidence and recurrence rates that still pose significant treatment challenges. Traditionally, it has been believed that estrogen and progesterone primarily drive the development and progression of uterine fibroids. Recent studies have revealed that hormonal imbalance can affect reactive oxygen species production and trigger a significant oxidative stress (OS) state. The OS status in uterine fibroids can further amplify the pathological effects caused by hormonal imbalance. This suggests that estrogen, progesterone, and OS may interact to form an estrogen-progesterone-oxidative stress (E-P-OS) network, collectively promoting the progression of uterine fibroids. This network model provides a theoretical basis for the high recurrence rates following hormone monotherapy or surgery. Therefore, we reviewed the molecular mechanisms underlying hormone-OS interactions within the E-P-OS network and elucidated its pathological effects in promoting uterine fibroid progression. The integrated perspective lays the theoretical foundation for developing novel therapies that simultaneously block hormone signaling and counteract oxidative damage. Additionally, we summarized current clinical strategies for hormone therapy and antioxidant treatment, identified potential combination therapy approaches, and explored key challenges in their clinical translation. This aims to provide new directions and evidence for advancing the precision treatment of uterine fibroids.
    Keywords:  Uterine fibroids; combination therapy; estrogen; molecular mechanisms; oxidative stress; progesterone; signaling network; targeted therapy
    DOI:  https://doi.org/10.1080/13510002.2026.2622747
  41. Sci Adv. 2026 Feb 06. 12(6): eadx9729
    Hybrid female sterility due to cohesin protection errors in mouse oocytes.
    Warif El Yakoubi, Bo Pan, Takashi Akera.
      Hybrid incompatibility can lead to lethality and sterility of F1 hybrids, promoting speciation. The cell biological basis underlying hybrid incompatibility remains largely unknown, especially in mammals. Here, we found that female hybrids between Mus musculus domesticus and Mus spicilegus mice are sterile due to the failure of homologous-chromosome separation in oocyte meiosis, producing aneuploid eggs. This nondisjunction phenotype was driven by the mislocalization of the cohesin protector, SGO2, along the chromosome arms instead of its typical centromeric enrichment, resulting in cohesin overprotection. The upstream kinase, BUB1, showed a higher activity in hybrid oocytes, explaining SGO2 mistargeting. Higher BUB1 activity was not observed in mitosis, consistent with viable hybrid mice. Cohesion defects were also evident in hybrid mice from another genus, Peromyscus, wherein cohesin protection is weakened. Defective cohesion in oocytes is a leading cause of reduced fertility. Our work provides evidence that a major cause of human infertility may play a positive role in mammalian speciation.
    DOI:  https://doi.org/10.1126/sciadv.adx9729
  42. Nat Immunol. 2026 Feb;27(2): 295-307
    γδ T cell-derived IL-4 initiates CD8+ T cell immunity.
    Shirley Le, Nick Dooley, Declan Murphy, Shangyi Liu, Luke C Gandolfo, Zhengyu Ge, Rose May, Anton Cozijnsen, Thomas N Burn, Charlie Jennison, Annabell Bachem, Calvin Xu, Hui-Fern Koay, Jan Schröder, Damian Oyong, Mayimuna Nalubega, Enny Kenangalem, Stephanie Gras, Ian A Cockburn, Sammy Bedoui, Laura K Mackay, Geoffrey I McFadden, Daniel Fernandez-Ruiz, Michelle Boyle, William R Heath, Lynette Beattie.
      Dendritic cells (DCs) are pivotal for initiating adaptive immunity, a process triggered by the activation of DCs via pathogen products or damage. Immunization with sporozoites from Plasmodium leads to CD8+ T cell priming in a response initiated by collaboration between conventional type 1 DCs (cDC1s) and γδ T cells. Here we show that Vγ1+ γδ T cells have an initiating role by directly supplying interleukin-4 (IL-4). IL-4 and interferon-γ (IFNγ) synergize with CD4+ T cell-derived CD40L to induce IL-12 production by cDC1. Both IL-12 and IL-4 then directly signal responding CD8+ T cells and drive enhanced IL-12 receptor expression and expansion. This study shows how Vγ1+ γδ T cells can initiate CD8+ T cell immunity to Plasmodium and that responses to some pathogens require help from innate-like T cells to pass an initiation threshold and further amplify the response in a process underscored by IL-4 production.
    DOI:  https://doi.org/10.1038/s41590-025-02397-z
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