bims-simsho 2025-11-02 papers

bims-simsho

Biomed News

on Systems immunology and sex hormones

Issue of 2025–11–02
twenty-six papers selected by
Chun-Chi Chang, Lunds universitet

Estrogen Receptor Regulates Male Satellite Cells in a Female, but Not Male, Environment.
Targeting the Androgen Receptor Pathway in Prostate Cancer: A PROTrACted Struggle.
Molecular pathogenesis, diagnosis, and management challenges in complete androgen insensitivity syndrome.
HOXA10 and HOXA11 Methylation: Epigenetic Barriers to Endometrial Receptivity in ART.
Molecular Impact of Metabolic and Endocrine Disturbance on Endometrial Function in Polycystic Ovary Syndrome.
Androgen receptor gene polymorphism and biological age markers in men.
Environmental toxins and toxic metals in autoimmune diseases: Sex differences, hormonal influences, and immune dysregulation.
The Gut Microbiota-Sex-Immunity Axis in Non-Communicable Diseases.
Liver Androgen Receptor Knockout Attenuates High-Fructose Diet-Induced Glucose Dysregulation in Female Mice.
TMPRSS2 Expression in Lung Tissue of Prostatic Adenocarcinoma Patients: Androgen Deprivation Therapy and Relevance to SARS-CoV-2 Infection.
Gender- and Grade-Dependent Activation of Androgen Receptor Signaling in Adult-Type Diffuse Gliomas: Epigenetic Insights from a Retrospective Cohort Study.
Sex Differences in Oxidative Stress Concerning Allergic Diseases.
Sexual dimorphism in colon is mediated by an androgen-IL33+ stromal cell axis.
Metabolic state shapes cortisol reactivity to acute stress: A systematic review and meta-analysis of metabolic and hormonal modulators.
From Gut to Reproductive Health: Exploring Microbiome Interactions and Future Interventions.
HER2 as a molecular trojan horse in prostate cancer: mechanistic insights and therapeutic unlocks.
Integrated proteomic and metabolomic analysis elucidates the effects and mechanisms of Qiziyusi decoction on IVF outcomes in advanced maternal age infertility.
Polycystic ovary syndrome: Unveiling the multifaceted contributors, mechanisms, and psychological impacts.
Sustained testosterone suppression: prognostic indicator in advanced hormone sensitive prostate cancer.
Targeting Polycystic Ovary Syndrome (PCOS) Pathophysiology with Flavonoids: From Adipokine-Cytokine Crosstalk to Insulin Resistance and Reproductive Dysfunctions.
Clustering of Uterine Natural Killer Cells Around Uterine Glands in Women with Recurrent Implantation Failure and Recurrent Pregnancy Loss: An Immunohistochemical Study.
Sex differences in CRSwNP: focus on histopathological endotypes and recurrence.
Neutrophils are key modulators of sex differences in LPS-induced shock in mice.
Analysis of the characteristics of endometrial fluid samples in recurrent pregnancy loss patients based on 16S rRNA gene sequencing technology.
Reframing Endometriosis: Interplay of NETs, Macrophages, and Lymphocytes at the Crossroads of Disease Progression, Infertility, and Malignant Transformation.
Lipid Metabolic Reprogramming During Progression to Castration-resistant Prostate Cancer Identified by Quantitative Proteomics.

Cells. 2025 Oct 16. pii: 1606. [Epub ahead of print]14(20):

Estrogen Receptor Regulates Male Satellite Cells in a Female, but Not Male, Environment.

Ahmed S Shams, Brian P Sullivan, Erik A Toso, Dawn A Lowe, Michael Kyba.

  Skeletal muscle homeostasis is dependent on the satellite cell pool, which is regulated by numerous signaling pathways. Estradiol (E2) function via estrogen receptor alpha (ERα, Esr1) plays an important role in satellite cell regulation in females, being necessary for satellite cell maintenance, proliferation and differentiation. Here we investigate this signaling axis in male satellite cells. Male satellite cells express Esr1 mRNA at similar levels to female satellite cells, and E2 enhances the proliferation of male satellite cell-derived myoblasts in vitro. Deletion of Esr1 specifically in male satellite cells has no effect on satellite cell number, nor on their ability to self-renew after injury, during regeneration, or when transplanted into male hosts. However, Esr1 deletion severely reduces self-renewal of male satellite cells when transplanted into female hosts. These data suggest that male satellite cells are competent for E2-ERα signaling, but that this signaling is not efficacious in the male environment, though E2-ERα signaling does become necessary when the male cells are transplanted into a female environment.

Keywords:  17β-estradiol; estrogen; estrogen receptor; regeneration; satellite cells; sex hormones; skeletal muscle; transplantation

DOI:  https://doi.org/10.3390/cells14201606
Clin Cancer Res. 2025 Oct 29.

Targeting the Androgen Receptor Pathway in Prostate Cancer: A PROTrACted Struggle.

Michael D Nyquist, Peter Nelson.

The Androgen Receptor (AR) is the most important therapeutic target for metastatic prostate cancer. Though clinical responses to AR inhibition are nearly universal, so is progression, usually accompanied by reactivation of AR signaling. A new small molecule dual AR degrader/inhibitor shows promise in overcoming resistance and improving clinical outcomes.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-3045
Front Endocrinol (Lausanne). 2025 ;16 1600343

Molecular pathogenesis, diagnosis, and management challenges in complete androgen insensitivity syndrome.

Chunqing Wang, Qinjie Tian.

  Complete androgen insensitivity syndrome (CAIS) is a rare X-linked recessive disorder of sex development (DSD) caused by androgen receptor (AR) gene mutation and present with female phenotypes with male chromosomal karyotype. Primitive bipotent gonads in CAIS differentiate into testes producing androgens and antimüllerian hormone (AMH). However, androgens cannot stimulate embryonic wolffian ducts into male internal reproductive organs owing to AR defect and hormone resistance, while AMH induces the regression of müllerian ducts with the absence of uterus, fallopian tubes, and upper third of the vagina. Thus, with male sex chromosome and testes, individuals with CAIS present with a typical female phenotype, primary amenorrhea (PA) and infertility, spontaneous thelarche during puberty, absent or sparse axillary/pubic hair, and increased risk of gonadal tumors in cryptorchidism. Though theoretically CAIS can be screened prenatally through a discrepancy between chromosomal karyotype and fetal external genitalia, suspected in bilateral inguinal "hernia" cases with female genital phenotype, and considered in cases with elevated testosterone (T) levels but no signs of virilization, the lack of typical symptoms brings great challenges to diagnosis and management. Endocrinological hormone assay is helpful for the identification of CAIS which reveals normal or elevated T levels, elevated luteinizing hormone for impairment of negative feedback of T, and normal follicle-stimulating hormone which is regulated by both sex hormones and inhibin. The diagnosis of CAIS after puberty is similar to the diagnostic workflow of PA with additional tests and should be differentiated with PA-related etiologies and other kinds of DSD, such as Swyer syndrome, Mayer-Rokitanskey-Küster-Haüser syndrome, Leydig cell hypoplasia, and several steroidogenic enzymatic deficiencies. Clinical manifestations, hormonal profiles, chromosomal karyotype, and pelvic imaging can provide comprehensive information for diagnosis. AR gene test or binding capacity can be performed for definitive diagnosis. The management of CAIS includes gonadectomy, hormone supplementation, and psychological support and education. Although with the development of molecular biology and awareness of the clinical entity more cases were reported, diagnostic and management challenges exist due to the disease-related and treatment-related stress including the rarity, untypical clinical manifestations, increased risk of gonadal malignancy, and its influence on physiology and psychology. This review provides a comprehensive overview of the molecular pathogenesis, pathophysiology, diagnostic evaluation, differential diagnosis, and management of CAIS.

Keywords:  androgen receptor; complete androgen insensitivity syndrome; disorders of sex development; gonadal development; sex assignment; sex determination; sexual differentiation

DOI:  https://doi.org/10.3389/fendo.2025.1600343
Genes (Basel). 2025 Oct 17. pii: 1230. [Epub ahead of print]16(10):

HOXA10 and HOXA11 Methylation: Epigenetic Barriers to Endometrial Receptivity in ART.

Dmitry Kudlay, Vsevolod Kiselev, Gennady Sukhikh.

  The global prevalence of infertility has reached critical levels, making it one of the most pressing issues in modern society. Assisted reproductive technologies (ARTs), particularly in vitro fertilization (IVF), are the primary treatment methods for infertility. However, even under optimal conditions, the pregnancy rate per IVF cycle does not exceed 40%, while the live birth rate remains around 30%. A key unresolved challenge in ART is impaired endometrial receptivity (ER), which significantly contributes to repeated implantation failure (RIF). Advances in molecular and genetic diagnostics have revealed that gynecological conditions associated with infertility, such as chronic endometritis, uterine fibroids, polycystic ovary syndrome (PCOS), and tuboperitoneal factor infertility, are often linked to epigenetic alterations. Specifically, abnormal hypermethylation of the promoter regions of the HOXA10 and HOXA11 genes has been observed in women of reproductive age with these conditions. Such epigenetic dysregulation negatively impacts ER and is associated with infertility. The methylation status of HOXA10 and HOXA11 may serve as a potential diagnostic marker for evaluating and treating infertility. These markers can be assessed using available molecular genetic techniques, including real-time PCR. A promising therapeutic approach to improve ER involves the use of epigallocatechin-3-gallate and indole-3-carbinol, which have been shown to demethylate and restore the expression of HOXA10 and HOXA11. Epigenetic regulation holds significant potential for enhancing the effectiveness of ART programs, offering new avenues for addressing infertility and improving reproductive outcomes. This review consolidates the current body of knowledge regarding the epigenetic regulation of endometrial receptivity. It outlines fundamental scientific data on epigenetic mechanisms and discusses contemporary diagnostic and pharmacological intervention strategies.

Keywords:  HOXA10; HOXA11; IVF; endometrial receptivity; epigallocatechin-3-gallate; epigenetic dysregulation; gene demethylation; indole-3-carbinol

DOI:  https://doi.org/10.3390/genes16101230
Int J Mol Sci. 2025 Oct 12. pii: 9926. [Epub ahead of print]26(20):

Molecular Impact of Metabolic and Endocrine Disturbance on Endometrial Function in Polycystic Ovary Syndrome.

Jim Parker, Claire O'Brien, Talat Uppal, Kelton Tremellen.

  Polycystic ovary syndrome (PCOS) is a systemic metabolic and endocrine disorder that significantly disrupts reproductive physiology and endometrial function. In this narrative review, we examine the molecular impact of metabolic and hormonal imbalances on the endometrium of women with PCOS. We investigate the specific mechanisms that delineate how hyperinsulinemia and insulin resistance, chronic low-grade inflammation, and estrogen/progesterone/androgen imbalance contribute to altered epigenetic, transcriptomic, metabolomic, and signaling profiles in a wide array of different cell types within endometrial tissues. The synergistic interplay between upregulated inflammatory cytokines (e.g., IL-1,2,6,8,17,18, and TNF-α), along with key changes in critical molecular pathways associated with hyperinsulinemia and insulin resistance (e.g., PI3K/AKT/MAPK, and Wnt/β-catenin), in addition to aberrant sex steroid hormone signaling (e.g., CYP19A1, COX-2, PGE2, HOXA10, 11βHSD2), promotes deleterious changes within the endometrial microenvironment. These anomalies underpin a spectrum of clinical manifestations observed in women with PCOS at each stage of the life course, including abnormal uterine bleeding in reproductive-age women, impaired decidualization in pregnancy, and altered postmenopausal endometrial physiology. Clinically, these alterations are associated with abnormal uterine bleeding, subfertility, implantation failure, miscarriage, pregnancy complications, and postmenopausal endometrial hyperplasia and cancer. Overall, our review provides novel insights into the molecular mechanisms linking systemic metabolic and endocrine dysfunction with endometrial pathology in PCOS and has broader implications that apply to all women.

Keywords:  cancer; decidualization; dysfunctional uterine bleeding; endocrine; endometrium; hormonal; metabolic; polycystic ovary syndrome; postmenopausal; pregnancy

DOI:  https://doi.org/10.3390/ijms26209926
Sci Rep. 2025 Oct 31. 15(1): 38226

Androgen receptor gene polymorphism and biological age markers in men.

Agnieszka Żelaźniewicz, Judyta Nowak-Kornicka, Adam Dąbrowski, Bogusław Pawłowski.

  Inter-individual differences in aging rates may stem from the trade-offs between reproductive effort and somatic maintenance, with higher reproductive effort potentially reducing healthspan and lifespan. In men, these trade-offs are thought to be regulated by androgens, where high androgen levels incur biological costs. However, the relationship between androgen levels, health, and aging is complex, and the role of androgen receptor (AR) sensitivity in aging remains unclear. Thus, this study aimed to investigate whether genetic polymorphisms in the AR gene, related to receptor affinity and androgen sensitivity, predict biological age in men. The analyses included 131 healthy men (mean age: 35.4, age range 30-45). Biological age was assessed using physiological markers, including klotho, inflammatory markers, oxidative stress, total antioxidant capacity, and DHEA/S levels. AR sensitivity was estimated based on CAG repeat length in exon 1 of the AR gene (AR CAGn), with shorter repeats indicating higher sensitivity. The independent effect of testosterone (T) level, as well as its potential interaction with AR CAGn, was also verified. Chronological age, body adiposity, lifestyle factors, and cortisol levels were controlled for. Results showed no relationship between AR CAGn and biological age markers, directly or through interaction with T levels. Findings suggest that lifetime testosterone fluctuations, influenced by environmental and health factors, may obscure the link between AR CAGn and reproductive/somatic investment, ultimately affecting the aging rate.

Keywords:  AR CAGn polymorphism; Aging; DHEA/S; Klotho; Receptor sensitivity; Trade-offs

DOI:  https://doi.org/10.1038/s41598-025-22090-3
Autoimmun Rev. 2025 Oct 29. pii: S1568-9972(25)00216-2. [Epub ahead of print] 103955

Environmental toxins and toxic metals in autoimmune diseases: Sex differences, hormonal influences, and immune dysregulation.

Geir Bjørklund, David R Wallace, Kimiya Kangarlou, Fahimida Hossain, Massimiliano Peana.

  Environmental toxins, including toxic metal(oid)s such as mercury, lead, cadmium, and arsenic, as well as endocrine-disrupting chemicals like bisphenol A and phthalates, play a critical role in the onset and progression of autoimmune diseases. These substances accumulate in biological tissues and disrupt immune homeostasis through oxidative stress, molecular mimicry, and epigenetic modifications, mechanisms that contribute to autoantibody production and chronic inflammation, hallmarks of autoimmunity. Women are disproportionately affected by autoimmune diseases due to inherent differences in immune function, hormonal regulation, and genetic susceptibility. Estrogen, a key immunomodulatory hormone, can amplify immune responses and promote autoantibody generation. Its interaction with environmental toxins further exacerbates immune dysregulation, increasing female vulnerability to conditions such as systemic lupus erythematosus, rheumatoid arthritis, and autoimmune thyroid disorders. Hormonal fluctuations during puberty, pregnancy, and menopause additionally influence toxin metabolism and detoxification efficiency, compounding the risk of immune imbalance and disease onset in women. This review synthesizes current evidence on the mechanisms through which environmental toxicants contribute to autoimmune pathogenesis, with particular focus on sex-specific vulnerabilities. It explores the role of hormonal-immune-environment interactions across the female lifespan and highlights emerging research on epigenetic inheritance, gut dysbiosis, and biomarker development. By integrating mechanistic, epidemiological, and clinical findings, this review aims to inform targeted strategies for prevention, early detection, and risk reduction of environmentally driven autoimmune diseases.

Keywords:  Autoantibodies; Autoimmune diseases; Environmental toxins; Epigenetics; Estrogen; Oxidative stress

DOI:  https://doi.org/10.1016/j.autrev.2025.103955
Life (Basel). 2025 Sep 25. pii: 1510. [Epub ahead of print]15(10):

The Gut Microbiota-Sex-Immunity Axis in Non-Communicable Diseases.

Mario Caldarelli, Pierluigi Rio, Laura Franza, Sebastiano Cutrupi, Martina Menegolo, Francesco Franceschi, Antonio Gasbarrini, Giovanni Gambassi, Rossella Cianci.

  Non-communicable diseases (NCDs), including cancer and autoimmune, metabolic, cardiovascular, and neurodegenerative diseases, represent the leading cause of death globally and a growing healthcare burden. The gut microbiota (GM) has been recognized as a key biological component of host health that contributes to the maintenance of immune regulation, metabolic homeostasis, and epithelial barrier function. Several studies are now demonstrating that biological sex has an influence on both GM composition and function, which might explain sex differences in disease predisposition, course, and treatment response. Evidence from both clinical and experimental studies indicates that sex hormones, genetics, and lifestyle-related exposures interact with GM to influence the development and progression of most common NCDs. Some research suggests that estrogens promote diversity in GM with anti-inflammatory immune responses, while androgens and male-abundant taxa are associated with pro-inflammatory conditions. However, the evidence in humans is largely confounded by other variables (such as age, genetics, and lifestyle) and should be interpreted with caution. Unique GM metabolites, such as short-chain fatty acids and secondary bile acids, can have distinct, sex-specific effects on inflammation, metabolic regulation, and even antitumor immunity. While the existence of a sex-gut microbiota axis is gaining increased support, most studies in humans are cross-sectional epidemiological studies with limited mechanistic evidence and little consideration for sex as a biological variable. Future works should prioritize longitudinal, sex-stratified studies and utilize multi-omics integrated approaches to identify causal pathways. Ultimately, integrating sex differences into GM-based approaches could provide new avenues for personalized strategies for the prevention and treatment of NCDs.

Keywords:  autoimmunity; cancer; gut microbiota; non-communicable diseases; precision medicine; sex differences

DOI:  https://doi.org/10.3390/life15101510
Am J Physiol Endocrinol Metab. 2025 Oct 25.

Liver Androgen Receptor Knockout Attenuates High-Fructose Diet-Induced Glucose Dysregulation in Female Mice.

Trinitee Oliver, Adjoa Osei-Ntansah, Claire Falzarano, Md Ahasanur Rahman, Taylor Lofton, Guyton Harvey, Stanley Andrisse.

  The Western diet, rich in fats and sugars such as fructose, contributes significantly to the global rise in obesity and type 2 diabetes. While both high-fat and high-fructose diets (HFD and HFrD) are known to impair hepatic insulin signaling, the specific mechanisms and potential sex-specific differences remain underexplored. Moreover, the role of hepatic androgen receptor (AR) in modulating these effects, particularly in females, has not been fully elucidated. Here, we investigated the contribution of hepatic AR to HFrD-induced metabolic dysfunction using liver-specific AR knockout (LivARKO) mice of both sexes. Male and female LivARKO and wild-type (WT) littermates were subjected to either a HFrD or calorie-matched control diet from 4 to 12 weeks of age and underwent several metabolic tests during months one and two. Glucose tolerance tests (GTT) conducted during month one revealed that WT-HFrD females developed significant glucose intolerance, while LivARKO-HFrD females exhibited partial protection, demonstrating improved glucose clearance relative to their WT counterparts. These effects appeared sex-specific, as male LivARKO mice did not exhibit similar protective effects under HFrD conditions. Our findings suggest that hepatic AR plays a sex-specific role in mediating fructose-induced insulin resistance, and its deletion in females confers partial protection against diet-induced metabolic impairments by improving hepatic insulin signaling and regulating gluconeogenic genes. This highlights the importance of considering sex and hepatic androgen signaling in the development of targeted therapies for diet-induced metabolic disorders.

Keywords:  Androgen receptor; fructose idet; insulin resistance; liver metabolism; sex differences

DOI:  https://doi.org/10.1152/ajpendo.00254.2025
Curr Issues Mol Biol. 2025 Oct 08. pii: 823. [Epub ahead of print]47(10):

TMPRSS2 Expression in Lung Tissue of Prostatic Adenocarcinoma Patients: Androgen Deprivation Therapy and Relevance to SARS-CoV-2 Infection.

Marcela Riveros Angel, David Loeffler, Ahmad Charifa, Ryan B Sinit, Taylor Amery, Beyza Cengiz, Tomasz M Beer, George V Thomas.

  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry is facilitated by transmembrane protease serine 2 (TMPRSS2), which is regulated by the androgen receptor (AR). Androgen deprivation therapy (ADT), widely used in prostate cancer treatment, may potentially modulate TMPRSS2 expression, affecting SARS-CoV-2 infection susceptibility and severity. We evaluated the impact of ADT on pulmonary TMPRSS2 expression in prostate cancer patients and analyzed differences in expression patterns associated with specific ADT regimens. We examined TMPRSS2 immunohistochemical expression in lung tissue from 20 consecutive autopsy cases of men with prostate cancer (6 receiving ADT at time of death), compared with non-ADT prostate cancer patients and age-matched women controls. Histoscores were calculated by assessing the percentage and intensity of pneumocyte TMPRSS2 expression. Prostate cancer patients receiving ADT showed significantly reduced pulmonary TMPRSS2 expression compared to non-ADT patients (mean histoscores: 152.7 vs. 225.0, p = 0.037) and age-matched women controls (mean histoscores: 152.7 vs. 238.0, p = 0.024). Direct AR antagonists (apalutamide, bicalutamide) produced greater TMPRSS2 suppression than Gonadotropin-Releasing Hormone modulators or androgen biosynthesis inhibitors. No significant correlation was observed between the TMPRSS2 expression and Gleason score, PSA levels, or underlying lung pathology. Our findings demonstrate that ADT significantly reduces pulmonary TMPRSS2 expression, with direct AR antagonists showing the strongest effect. This suggests a potential mechanistic explanation for differential COVID-19 susceptibility and provides a rationale for investigating AR-targeted therapies as potential protective interventions against SARS-CoV-2 infection severity.

Keywords:  SARS-CoV-2; TMPRSS2; androgen deprivation therapy (ADT); androgen receptor (AR); prostate

DOI:  https://doi.org/10.3390/cimb47100823
Biomedicines. 2025 Sep 28. pii: 2379. [Epub ahead of print]13(10):

Gender- and Grade-Dependent Activation of Androgen Receptor Signaling in Adult-Type Diffuse Gliomas: Epigenetic Insights from a Retrospective Cohort Study.

Lidia Gatto, Sofia Asioli, Luca Morandi, Enrico Di Oto, Vincenzo Di Nunno, Alicia Tosoni, Marta Aprile, Stefania Bartolini, Lucia Griva, Sofia Melotti, Francesca Gentilini, Giuseppe Pinto, Francesco Casadei, Maria Pia Foschini, Caterina Tonon, Raffaele Lodi, Enrico Franceschi.

  Background: The androgen receptor (AR) is a ligand-dependent transcription factor of the nuclear steroid receptor superfamily, implicated in the pathogenesis of various solid tumors. The AR gene, located on chromosome Xq11-12, is accompanied by several X-linked genes that modulate AR expression and function, including FLNA, UXT, and members of the melanoma antigen gene (MAGE) family (MAGEA1, MAGEA11, MAGEC1, MAGEC2). While the AR has been investigated in multiple tumor types, its role in adult-type diffuse gliomas remains largely unexplored. Here, we characterized AR protein expression and the promoter methylation status of the AR and associated regulatory genes in adult-type diffuse gliomas. Methods: A retrospective analysis was conducted on 50 patients with adult-type diffuse gliomas, including IDH-mutant gliomas (grades 2-4) and IDH-wildtype glioblastomas (GBMs), classified according to the 2021 WHO criteria. AR nuclear expression was assessed by immunohistochemistry (IHC). Methylation-specific PCR and quantitative DNA methylation analyses were employed to evaluate promoter methylation of the AR and selected co-regulatory genes. Results: AR nuclear positivity correlated significantly with male sex (p = 0.04) and higher tumor grade, with the highest expression in IDH-wildtype GBMs (p = 0.04). In IDH-mutant gliomas, AR immunoreactivity was more prevalent in astrocytomas than in 1p/19q codeleted oligodendrogliomas (p = 0.02). AR expression was associated with unmethylated MGMT promoter status (p = 0.02). DNA methylation analysis revealed AR gene hypomethylation in tumors displaying nuclear AR positivity and in IDH-wildtype GBMs (Kruskal-Wallis p < 0.05). Additionally, methylation patterns of AR co-regulators located on the X chromosome suggest epigenetic regulation of AR signaling in gliomas. Conclusions: The findings reveal distinct AR pathway activation patterns in adult-type diffuse gliomas, particularly IDH-wildtype GBMs, suggesting that further exploration of antiandrogen therapies is warranted.

Keywords:  DNA methylation; androgen receptor; enzalutamide; glioblastoma; glioma

DOI:  https://doi.org/10.3390/biomedicines13102379
Biomolecules. 2025 Oct 16. pii: 1461. [Epub ahead of print]15(10):

Sex Differences in Oxidative Stress Concerning Allergic Diseases.

Mattia Cristallo, Fabiana Furci, Marco Casciaro, Sebastiano Gangemi, Eustachio Nettis.

  In recent years, the role of sexual hormones in the pathogenesis and progression of various diseases has progressively being established, which attempts to explain immune dimorphism. Whether physiological or pathological, variations in hormones influence the inflammatory response and adaptive systems to control increased productions of reactive oxygen species, reactive nitrogen species, and free radicals. Primary allergic respiratory and skin diseases were taken into consideration, and possible biomarkers of oxidative stress related to sex differences in the onset and development of atopic diseases were analyzed. Understanding how these variables interact with each other, and evaluating the possible common targets, lays the foundation for the development of tailored therapies with an eye to precision medicine.

Keywords:  allergic contact dermatitis; allergic rhinitis; antioxidant; asthma; atopic dermatitis; gender differences; oxidative stress; sex hormones; urticaria

DOI:  https://doi.org/10.3390/biom15101461
Cell Biosci. 2025 Oct 29. 15(1): 148

Sexual dimorphism in colon is mediated by an androgen-IL33+ stromal cell axis.

Haoyu Wang, Baowei Jing, Juan Zou, Tian Lan, Mengxin Hu, Lan Lin, Hanhua Cheng, Rongjia Zhou.

   BACKGROUND: Males and females exhibit pronounced disparity in the epidemiology, clinical progression, and therapeutic outcomes of colonic diseases, but the underlying mechanisms that regulate sexual dimorphism of colon remain poorly understood.
RESULTS: We determined the colon as a pivotal androgen metabolic hub, where gonad-derived androgens drive sex-dimorphic levels, while androgen-metabolizing enzymes maintain androgen homeostasis in colon. We identified IL-33+ colonic stromal cells as the dominant AR-expressing population in colon. Mechanistically, sex-biased androgen levels govern the nuclear translocation of androgen receptor and further assembly of AR liquid-liquid phase-separated condensates in the immunomodulatory stromal cells of male colon. Notably, we uncovered AR-directed transcriptional programs via nuclear AR phase separation underlying sex-biased expression of key factors, including SerpinA3N and MT1, thereby defining molecular base for sex disparities through gonad-colon axis.
CONCLUSION: These findings provide molecular and cellular base for sex disparities through an androgen-IL33+ stromal cell axis in colon.

Keywords:  Androgen receptor; Colon; Disparity; Gonad; Sex

DOI:  https://doi.org/10.1186/s13578-025-01493-9
Neurobiol Stress. 2025 Nov;39 100764

Metabolic state shapes cortisol reactivity to acute stress: A systematic review and meta-analysis of metabolic and hormonal modulators.

Madeleine Kördel, Maria Meier, Anne Kühnel, Nils B Kroemer.

  Individual variability in cortisol stress responses is shaped by multiple physiological factors. Yet the interaction with metabolic and hormonal states remains poorly understood. Therefore, we conducted a systematic review and meta-analysis to examine how metabolic factors (particularly glucose) and sex hormone levels (progesterone and estradiol) influence cortisol reactivity to acute stress. We identified 21 studies (N = 1216 participants) and conducted random-effects meta-analyses for metabolic and hormonal states. Across studies, glucose administration was associated with a significant increase in cortisol responses to acute stress compared to fasting or non-glucose control conditions (d = 0.30, 95 % CI = [0.05, 0.60], BF10 = 2.42, NNT = 10.63). In contrast, the effects of sex hormones on cortisol responses were smaller and more variable, with both progesterone and estradiol showing weak and inconsistent associations. Our results highlight a robust modulatory role of metabolic state, specifically glucose availability, on HPA axis reactivity, while evidence for sex hormone effects remains inconclusive. Future research should focus on better harmonization of designs concerning sex hormones and systematically examine interactions between metabolic and hormonal states to better explain sex differences in the prevalences of metabolic and stress-related disorders.

Keywords:  Cortisol; Estradiol; Glucose; HPA axis; Meta-analysis; Metabolic state; Progesterone; Sex hormones; Stress reactivity

DOI:  https://doi.org/10.1016/j.ynstr.2025.100764
Reprod Sci. 2025 Oct 31.

From Gut to Reproductive Health: Exploring Microbiome Interactions and Future Interventions.

Samradhi Singh, Mona Kriti, Poonam Sharma, Namrata Pal, Devojit Kumar Sarma, Vinod Verma, Rajnarayan R Tiwari, Manoj Kumar.

  Recent advances in microbiome research have illuminated the complex bidirectional interactions between gut health and reproductive well-being. Understanding the gut microbiome's influence on the reproductive system and vice versa reveals how both of them can affect hormone production, immune function, and ultimately overall reproductive health. Dysbiosis, an imbalance in the gut microbial community, has been linked with a range of reproductive issues, including decreased sperm count and motility, erectile dysfunction, polycystic ovary syndrome (PCOS), endometriosis, infertility, and adverse pregnancy outcomes. This review critically evaluates emerging therapeutic interventions aimed at restoring microbial balance and enhancing reproductive health, such as use of prebiotics, probiotics, bacteriophage therapy, and fecal microbiota transplantation (FMT). By exploring the intricate interplay between gut microbiota and reproductive health, this review also emphasizes the need for integrated approaches in research and clinical practice to develop effective microbiome-based therapies for better reproductive health outcomes.

Keywords:  Bacterial vaginosis; Endometriosis; Gut microbiome; PCOS; Reproductive health

DOI:  https://doi.org/10.1007/s43032-025-02001-7
Mol Biol Rep. 2025 Oct 30. 53(1): 31

HER2 as a molecular trojan horse in prostate cancer: mechanistic insights and therapeutic unlocks.

Anirban Goutam Mukherjee, Abilash Valsala Gopalakrishnan.

  Human epidermal growth factor receptor 2 (HER2/ERBB2) is a well-established therapeutic target in breast and gastric cancers, but its relevance in prostate cancer (PC) remains unresolved. Although HER2 gene amplification is relatively uncommon in PC, heterogeneous overexpression has been observed, particularly in advanced and castration-resistant PC (CRPC), where it is frequently associated with aggressive clinicopathological features. Experimental studies portray HER2 as a signaling hub, mediating crosstalk with androgen receptor (AR) signaling to sustain tumor growth under androgen-deprived conditions. Concurrent activation of the HER2-PI3K-AKT axis further promotes cell survival, proliferation, and therapeutic adaptation. Moreover, HER2 cooperates with epidermal growth factor receptor (EGFR) and NF-κB pathways, reinforcing tumor plasticity and resistance mechanisms. Despite these compelling biological insights, clinical translation has been disappointing. Early trials with Trastuzumab, Lapatinib, and Pertuzumab yielded minimal benefit, underscoring patient heterogeneity, pathway redundancy, and the lack of biomarker-guided stratification. Lessons from these failures highlight the need for precision oncology approaches that integrate molecular profiling and rational therapeutic combinations. Recent advances, including next-generation HER2-targeted antibody-drug conjugates, bispecific antibodies, and CAR-T cell therapies, as well as strategies combining HER2 inhibition with AR signaling blockade, PI3K/AKT inhibitors, or immunotherapy, offer renewed promise. HER2 in PC thus represents a paradox: biologically significant but clinically underexploited. Reframing HER2 within the AR-PI3K signaling network and leveraging biomarker-driven strategies may finally unlock its therapeutic potential. This review critically examines HER2 in PC, analyzing its mechanistic roles, therapeutic potential, and the challenges that shape its value as both a prognostic biomarker and actionable target.

Keywords:  Androgen receptor; HER2; PI3K/AKT pathway; Prostate cancer; Therapeutic resistance

DOI:  https://doi.org/10.1007/s11033-025-11202-x
Front Endocrinol (Lausanne). 2025 ;16 1573206

Integrated proteomic and metabolomic analysis elucidates the effects and mechanisms of Qiziyusi decoction on IVF outcomes in advanced maternal age infertility.

Qingmei Jin, Jianyun Zhao, Yingjie Ma, Yi Zhang, Menghan Yan, Jingyan Song, Xianling Cao, Zhengao Sun.

   Background: Advanced maternal age (AMA) is associated with increased infertility and poor outcomes of in vitro fertilization (IVF), with limited effective treatments available. The traditional Chinese medicine (TCM) formula Qiziyusi decoction (QZYSD) is promising for addressing infertility in older women; however, its effects and mechanisms on IVF outcomes remain poorly understood. This study integrated a prospective cohort study, proteomics, and metabolomics to elucidate the effects and mechanisms by which QZYSD improves IVF outcomes in AMA infertility.
Methods: This prospective cohort study included 87 patients with tubal factor infertility who underwent IVF at the Reproductive and Genetic Center of Shandong University of TCM from April 2019 to October 2020, and stratified according to maternal age into the AMA (≥ 35 and ≤ 41), AMA-QZYSD (≥ 35 and ≤ 41), and young maternal age (YMA; ≥ 21 and ≤ 27) groups. The three groups of patients underwent controlled ovarian hyperstimulation using a short luteal phase protocol. In the AMA-QZYSD group, patients started oral administration of QZYSD from the day of pituitary downregulation until the day of oocyte retrieval, and follicular fluid (FF) was collected from all groups. The effects of QZYSD on improving IVF outcomes in AMA infertility were evaluated primarily by assessing cumulative clinical pregnancy (CCP) and miscarriage (CCM) rates, with secondary endpoints including the duration and dosage of gonadotropin (Gn) use, serum levels of follicle stimulating hormone (FSH), luteinizing Hormone (LH) and estrogen (E2) after pituitary downregulation, serum levels of E2 and progesterone (P) on the day of human chorionic gonadotropin (hCG) administration, endometrial thickness (EMt), number of oocytes retrieved, fertilization and cleavage rates, number of high-quality embryos on day 3, and embryo freezing status. Differential metabolites and proteins in FF were detected using ultra-performance liquid chromatography-tandem mass spectrometry and label-free quantitative proteomics. Correlation analysis was conducted to identify metabolites and proteins with significant correlations, and potential pathways were enriched and constructed using the common pathway analysis function in MetaboAnalyst (version 5.0). Finally, a "core target protein-metabolite-signaling pathway" network diagram was constructed using Cytoscape to further elucidate the mechanisms by which QZYSD improves IVF outcomes in patients with AMA infertility.
Results: The study included 87 patients in the AMA-QZYSD experimental (n = 28), AMA control (n = 28), and YMA (n = 31) groups. The baseline demographic and clinical characteristics, such as maternal and paternal age, antral follicle count, basal serum levels of FSH, and E2 levels, were comparable across the groups. Regarding the primary endpoint, there was a trend toward a higher CCP rate in the AMA-QZYSD group compared to the AMA group. However, this difference was statistically non-significant (53.57% vs. 39.29%, P = 0.28), while the CCP rate in the AMA group was significantly lower than in the YMA group (P < 0.05). The CCM rates indicated non-significant differences among the three groups (P > 0.05). For the secondary endpoint, serum levels of E2 on the day of HCG (2391.57 ± 985.09 versus 1833.39 ± 763.49, P = 0.04), the number of retrieved oocytes (9.18 ± 3.90 versus 7.07 ± 2.92, P = 0.04) and high-quality embryos on day 3 (1.86 ± 1.58 versus 1.04 ± 1.20, P = 0.05) were slightly higher in the AMA-QZYSD group compared to the AMA control group, but both were lower than the YMA group (P < 0.05). There were non-significant differences between the AMA-QZYSD and AMA groups regarding Gn usage days, Gn dosage, serum levels of FSH, LH and E2 after pituitary downregulation, serum levels of P on the day of hCG administration, EMt, IVF 2PN fertilizations, and embryo freezing status (P > 0.05). A total of 35 differentially abundant metabolites were identified through metabolomics, and 492 differential proteins were detected using proteomics. The integrated metabolomics and proteomics results suggested that QZYSD may improve IVF outcomes in AMA infertility primarily by regulating the expression of component C8 alpha chain (C8A), carboxypeptidase B2 (CPB2), serum paraoxonase/arylesterase 1 (PON1), immunoglobulin heavy variable 3-9 (IGHV3-9) and pantetheinase (VNN1), as well as influencing the protein digestion and absorption and pantothenate and coenzyme A biosynthesis pathways.
Conclusion: QZYSD in IVF for women with AMA infertility is promising for improving clinical pregnancy rates and overall IVF outcomes, potentially through its effect on the FF microenvironment. However, further research is needed to conduct larger randomized controlled double-blind clinical trials and experimental studies to elucidate the efficacy and mechanisms of QZYSD on IVF success in this population.

Keywords:  IVF; TCM (traditional Chinese medicine); advanced maternal age; follicular fluid (FF); outcome

DOI:  https://doi.org/10.3389/fendo.2025.1573206
Horm Behav. 2025 Oct 28. pii: S0018-506X(25)00170-9. [Epub ahead of print]176 105844

Polycystic ovary syndrome: Unveiling the multifaceted contributors, mechanisms, and psychological impacts.

Prerna Bhati, Prakash Haloi, Kavita Munjal, Havagiray R Chitme.

  Polycystic ovary syndrome (PCOS), also known as Stein-Leventhal syndrome, is a prevalent endocrine disorder affecting 6-13 % of women of reproductive age, with a significant proportion remaining undiagnosed. Characterized by hyperandrogenism, menstrual irregularities, and ovarian dysfunction, PCOS has extensive dermatological and metabolic implications, often contributing to adverse mental health outcomes. While depression and anxiety are commonly reported, distinguishing their etiology from obesity's frequent comorbidity with PCOS remains challenging. Emerging evidence suggests that hyperandrogenism may also influence the prevalence of schizophrenia, eating disorders, and neurodevelopmental conditions such as attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Prenatal androgen exposure has been implicated in neurodevelopmental alterations, with recent studies linking maternal PCOS to an increased risk of ASD in offspring. Structural brain differences, including white matter alterations, have also been observed in affected individuals. This review explores the intricate interplay between PCOS, metabolic dysfunction, and neuropsychiatric outcomes, emphasizing the need for further investigation into its neurodevelopmental and psychiatric implications. Additionally, we will explore the relationships between hormonal interplay and ASD, further elucidating the role of endocrine dysregulation in neurodevelopment.

Keywords:  Autism spectrum disorder (ASD); Depression; Hyperandrogenism; Insulin resistance; Neuroendocrine signalling; Psychological impact

DOI:  https://doi.org/10.1016/j.yhbeh.2025.105844
Front Endocrinol (Lausanne). 2025 ;16 1652941

Sustained testosterone suppression: prognostic indicator in advanced hormone sensitive prostate cancer.

Dongsheng Ma, Tao Zhuo, Xin Huang, Jianhong Xi.

   Objective: We aimed to investigate the relationship between sustained testosterone suppression and clinical outcomes in advanced hormone-sensitive prostate cancer (aHSPC), which integrates longitudinal testosterone with castration duration to predict tumor progression and prognosis.
Methods: In this retrospective study, we analyzed 336 patients with aHSPC from two medical centers who underwent serial testosterone monitoring during androgen deprivation therapy (ADT). The patients were stratified by testosterone suppression sustainability into the testosterone sustained response and testosterone non-sustained response groups. We evaluated the baseline characteristics, time to progression (TTP), and the survival outcomes between groups.
Results: The cohort demonstrated a median TTP of 18 months and an overall survival of 6.17 years. Patients in the testosterone sustained response group showed significantly better outcomes than those in the testosterone non-sustained response group, with longer median survival (7.58 vs. 3.00 years, p<0.001) and TTP (23.70 ± 14.66 vs. 13.68 ± 7.84 months, p < 0.001). Inverse correlations emerged between minimum testosterone and TTP (r = -0.238, p < 0.001) and between average testosterone and TTP (r = -0.220, p < 0.001). Multivariate analysis identified visceral metastases (adjusted OR = 0.45, 95%CI = 0.21-0.98, p=0.043) and high tumor load (adjusted OR = 0.53, 95%CI = 0.33-0.85, p = 0.008) as negative predictors of testosterone stabilization. The testosterone sustained response group status predicted reduced mortality risk (adjusted HR = 0.605, 95%CI = 0.369-0.990, p = 0.045), while higher minimum testosterone increased the mortality risk (adjusted HR = 1.358, 95%CI = 1.116-1.654, p = 0.002).
Conclusion: Sustained testosterone suppression provides a clinically applicable method for assessing treatment efficacy and predicting prognosis in aHSPC.

Keywords:  advanced hormone sensitive prostate cancer; androgen deprivation therapy; castration; testosterone monitoring; testosterone suppression

DOI:  https://doi.org/10.3389/fendo.2025.1652941
Pharmaceuticals (Basel). 2025 Oct 18. pii: 1575. [Epub ahead of print]18(10):

Targeting Polycystic Ovary Syndrome (PCOS) Pathophysiology with Flavonoids: From Adipokine-Cytokine Crosstalk to Insulin Resistance and Reproductive Dysfunctions.

Sulagna Dutta, Pallav Sengupta, Sowmya Rao, Ghada Elsayed Elgarawany, Antony Vincent Samrot, Israel Maldonado Rosas, Shubhadeep Roychoudhury.

  Polycystic ovary syndrome (PCOS) represents one of the most prevalent endocrine-metabolic disorder in women of reproductive age, which includes but not restricted to reproductive disruptions, insulin resistance (IR), hyperandrogenism, and chronic low-grade inflammation. Its heterogeneous pathophysiology arises from the interplay of metabolic, endocrine, and immune factors, including dysregulated adipokine secretion, cytokine-mediated inflammation, oxidative stress (OS), and mitochondrial dysfunction. Current pharmacological therapies, such as metformin, clomiphene, and oral contraceptives, often provide partial benefits and are limited by side effects, necessitating the exploration of safer, multi-target strategies. Flavonoids, a structurally diverse class of plant-derived polyphenols, have gained attention as promising therapeutic candidates in PCOS due to their antioxidant, anti-inflammatory, insulin-sensitizing, and hormone-modulating properties. Preclinical studies in rodent PCOS models consistently demonstrate improvements in insulin sensitivity, normalization of ovarian morphology, restoration of ovulation, and reduction in hyperandrogenism. Human clinical studies, though limited in scale and heterogeneity, report favorable effects of flavonoids such as quercetin, isoflavones, and catechins on glucose metabolism, adipokine balance, inflammatory markers, and reproductive functions. This evidence-based study critically synthesizes mechanistic insights into how flavonoids modulate insulin signaling, adipokine-cytokine crosstalk, OS, and androgen excess, while highlighting translational evidence and emerging delivery systems aimed at overcoming bioavailability barriers. Collectively, flavonoids represent a promising class of nutraceuticals and adjuncts to conventional therapies, offering an integrative strategy for the management of PCOS.

Keywords:  adipokine secretion; catechins; cytokine-mediated inflammation; insulin resistance; isoflavones; polycystic ovary; quercetin

DOI:  https://doi.org/10.3390/ph18101575
Int J Mol Sci. 2025 Oct 17. pii: 10109. [Epub ahead of print]26(20):

Clustering of Uterine Natural Killer Cells Around Uterine Glands in Women with Recurrent Implantation Failure and Recurrent Pregnancy Loss: An Immunohistochemical Study.

Lenka Lapides, Martin Klein, Ivan Varga, Jaroslav Voller, Pavel Babal.

  The immunological factor of sterility, specifically the abnormal count and activity of uterine NK (uNK) cells, may represent one of the potential contributors affecting specific subgroups of sterile couples undergoing assisted reproductive treatment (ART). Therefore, the primary purpose of the present paper was to assess uNK cell count. A total of 387 endometrial biopsies from patients with recurrent implantation failure (RIF) or recurrent pregnancy loss (RPL) were analyzed to identify abnormalities in uNK cell count, using immunohistopathological evaluation. ANOVA analysis revealed a strong association with factor 0.161 with p-value < 0.01, indicating that higher uNK cell count is associated with the presence of clusters (multicellular aggregates of uNK cells). These results suggest that the formation of clusters and the spatial distribution of uNK cells are significant factors in the context of the aforementioned clinical questions. However, the actual translational potential to clinical practice has not yet been established due to several challenges, namely: 1. the constantly changing definitions and diagnostic criteria for RIF and RPL, 2. varying sampling approaches for uNK cells, and 3. the historical lack of clear differentiation between uterine and peripheral NK cells. When all these issues are resolved, the observed tendency of uNK cells to form clusters will need to be a central focus of future investigations addressing RIF and RPL, thus improving ART outcomes.

Keywords:  assisted reproductive treatment; immunohistochemistry; recurrent implantation failure; recurrent pregnancy loss; uNK cell clusters

DOI:  https://doi.org/10.3390/ijms262010109
Rhinology. 2025 Oct 27.

Sex differences in CRSwNP: focus on histopathological endotypes and recurrence.

W Chen, H Wang, D Wang, W Li, Y Li, J Chen, Q Yang, Y Zhang.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) exhibits sex-specific differences in prevalence and clinical presentation. However, the underlying histopathological characteristics and recurrence remain underexplored.
METHODOLOGY: A retrospective cohort of 410 CRSwNP patients (287 males, 123 females) undergoing endoscopic sinus surgery between January 2021 and June 2024 was analyzed. Histological evaluation was employed by H&E staining and features of inflammatory profile were identified by immunohistochemistry. Multivariate logistic regression and receiver operating characteristic analyses were performed to assess predictors of recurrence.
RESULTS: Males exhibited higher body mass index (BMI) and greater allergic rhinitis prevalence, while females had more asthma comorbidity and higher SNOT-22 scores. While no significant sex differences were observed in histopathological endotypes, elevated BMI was more likely to exacerbate inflammation in males than females. Additionally, males showed a higher recurrence rate, with male sex being identified as an independent risk factor. However, females who experienced recurrence exhibited more severe eosinophilic and T2 inflammation compared to their male counterparts. Therefore, higher threshold values for tissue eosinophil counts and Charcot-Leyden crystals were required to predict recurrence in female patients.
CONCLUSIONS: These findings underscore the necessity for sex tailored therapeutic strategies, particularly emphasizing weight control in male patients and intensified anti-T2 inflammation management in female patients with recurrent CRSwNP. Further research is needed to investigate the underlying causes and to offer evidence-based treatment guidelines.

DOI: https://doi.org/10.4193/Rhin25.348
Blood Vessel Thromb Hemost. 2025 Nov;2(4): 100104

Neutrophils are key modulators of sex differences in LPS-induced shock in mice.

Prabuddha Sarkar, Lalita Mazgaeen, Saurabh Saini, Neelam Gautam, Austin Paden, Hanna Paton, Parker Boevers, Julia Duvall, Corey Parlet, Jennifer Bermick, Prajwal Gurung.

Lipopolysaccharide (LPS) exposure in mice induces robust morbidity and mortality, and is widely used as a model for sepsis. However, the role of biological sex in modulating immune responses during LPS-induced sepsis remains incompletely understood. In this study, we investigated how sex influences immune responses following LPS challenge in mice. Using age-matched mice, we found that during primary LPS challenge, females exhibited significantly higher mortality than males. This difference correlated with greater production of proinflammatory cytokines in females. Further analysis revealed that female myeloid cells expressed higher levels of Toll-like receptor 4, and displayed enhanced activation of NF-κB and MAPK signaling. Additionally, compared with males, female macrophages expressed significantly more inducible nitric oxide synthase but less arginase, supporting a sex-based divergence in inflammatory response to LPS. Interestingly, during lethal LPS rechallenge, the sex bias was reversed, with higher mortality observed in males than in females. These findings suggest that males had a survival advantage during the primary LPS challenge, while females exhibited greater resistance during rechallenge, emphasizing the need for careful consideration of sex-based differences in sepsis models. Neutrophils played a critical role in these sex-based differences. Neutrophil depletion significantly increased susceptibility to both primary and secondary LPS challenge. Notably, the sex bias in LPS-induced shock disappeared in neutrophil-depleted mice, highlighting a previously unrecognized role for neutrophils in mitigating LPS-induced mortality and maintaining sex-based differences in sepsis outcome.

DOI: https://doi.org/10.1016/j.bvth.2025.100104
Front Cell Infect Microbiol. 2025 ;15 1646125

Analysis of the characteristics of endometrial fluid samples in recurrent pregnancy loss patients based on 16S rRNA gene sequencing technology.

Xiaoping Wang, Nan Ding, Xiaofeng Li, Menghao Lu, Peili Wang.

   Introduction: Recurrent pregnancy loss (RPL) is a complex condition with multifactorial causes. This study aimed to characterize the microbial composition of endometrial fluid in RPL patients compared with healthy controls.
Methods: A total of 114 participants were recruited from the Second Hospital of Lanzhou University between March and September 2023, including 68 RPL patients and 46 healthy controls. Clinical data and endometrial fluid samples were collected. Microbial DNA was extracted and analyzed using 16S rRNA gene sequencing. Microbial diversity was assessed with QIIME, semi-partial correlation analysis was applied to explore associations between groups, and LEfSe was used to identify differentially abundant taxa.
Results: No significant differences in alpha diversity indices were found between the groups (p>0.05). However, beta diversity showed significant differences (p<0.05), indicating distinct microbial compositions. At the genus level, Vibrio and Pseudoalteromonas were positively correlated with RPL, suggesting their potential role in the condition. LEfSe analysis further validated our results, highlighting several taxa with significant differences in abundance, indicating microbial imbalances in RPL patients.
Discussion: The study emphasizes the impact of microbial imbalances on reproductive health, potentially aiding in the development of targeted interventions to restore microbial balance and improve pregnancy outcomes in RPL patients.

Keywords:  16S rRNA; endometrial fluid; microbial dysbiosis; microbiota; recurrent pregnancy lose

DOI:  https://doi.org/10.3389/fcimb.2025.1646125
Am J Reprod Immunol. 2025 Nov;94(5): e70179

Reframing Endometriosis: Interplay of NETs, Macrophages, and Lymphocytes at the Crossroads of Disease Progression, Infertility, and Malignant Transformation.

Megha M Anchan, Rahul Dutta.

  Endometriosis (ENDO) is a painful, chronic gynecological disease widely affecting women globally. While traditionally classified as a hormonal disorder, ENDO is now increasingly recognized as a multifaceted immune-mediated syndrome driven by chronic inflammation and immune tolerance. It is associated with painful symptoms, infertility, and potential malignant transformation. This study provides a comprehensive review of the immunological literature from electronic databases, focusing on the roles of innate and adaptive immune cell dysfunction in ENDO progression, including Neutrophil Extracellular Traps (NETs), macrophages, and lymphocytes. The pathology is governed by a dysregulated immunological landscape, specifically involving elevated NETs, the prevalence of immunosuppressive M2 macrophages, and compromised Natural Killer (NK) cell and T lymphocyte activity. These elements establish a tumor-like microenvironment through the activation of immune checkpoints and metabolic reprogramming. The chemokine IL-8 is highlighted as a central catalyst promoting NETosis and inflammation, driving fibrosis, lesion invasiveness, and reproductive failure. These immune circuits may also contribute to the risk of Endometriosis-Associated Ovarian Cancers. Reframing ENDO through this immunological paradigm provides an integrated model that incorporates its inflammatory, fibrotic, and carcinogenic features. This understanding reveals promising, non-hormonal therapeutic strategies targeting NETs, macrophage modulators, and immunological checkpoints for disease management and fertility preservation.

Keywords:  EAOCs; ENDO; IL‐8; NETs; NK cell; macrophage

DOI:  https://doi.org/10.1111/aji.70179
Cancer Genomics Proteomics. 2025 Nov-Dec;22(6):22(6): 940-952

Lipid Metabolic Reprogramming During Progression to Castration-resistant Prostate Cancer Identified by Quantitative Proteomics.

Hyunchae Sim, Subin Bae, Chai Won Park, So Young Choi, Kwang-Hyeon Liu, Eun Hye Lee, Bum Soo Kim, Jae-Wook Chung, Yun-Sok Ha, Jun Nyung Lee, Wonhwa Lee, Tae Gyun Kwon, Sangkyu Lee.

   BACKGROUND/AIM: The progression of hormone-sensitive prostate cancer (HSPC) to castration-resistant prostate cancer (CRPC) as a result of resistance to androgen deprivation therapy (ADT) remains a major challenge in prostate cancer treatment.
MATERIALS AND METHODS: To explore the underlying mechanisms, we performed deep comparative proteomic profiling of HSPC and CRPC cell lines. LNCaP and C4-2 cell lines were cultured in isotopically labeled medium, combined, and digested, followed by liquid chromatography-mass spectrometry (LC-MS/MS) and bioinformatic analyses.
RESULTS: Using SILAC-based proteomic analysis, 3,578 proteins were identified, with 2,474 quantified. In C4-2 cells, 41 proteins were significantly up-regulated, while 201 were down-regulated (fold-change >1.5 or <1.5-1, p<0.05). KEGG pathway analysis linked the increased proteins to fatty acid metabolism and biosynthesis of unsaturated fatty acids. Lipidomic analysis showed a significant rise in fatty acids like DHA, palmitic acid, stearic acid, and arachidic acid, aligning with the proteomic findings.
CONCLUSION: These results suggest that fatty acids play a key role in HSPC's progression to CRPC, possibly indicating that CRPC cells themselves may generate fatty acids.

Keywords:  Prostate cancer; castration-resistant prostate cancer; lipid metabolism; proteomics

DOI:  https://doi.org/10.21873/cgp.20548