bims-simsho 2025-09-28 papers

bims-simsho

Biomed News

on Systems immunology and sex hormones

Issue of 2025–09–28
28 papers selected by
Chun-Chi Chang, Lunds universitet

Androgen receptor signaling as a new target for intervention in acute myeloid leukemia.
Sex differences in preterm cytokine and inflammasome responses and modulation by exogenous sex steroids.
Sex Steroids in COVID-19 Patients with Hypertension: An Exploratory Study.
Molecular Signatures of Obesity-Associated Infertility in Polycystic Ovary Syndrome: The Emerging Role of Exosomal microRNAs and Non-Coding RNAs.
Infertility and Auto-Antibodies: A Review.
The relationship between initial vitamin D levels and in vitro fertilization (IVF) outcomes in PCOS patients: a systematic review.
Alteration of the follicular fluid amino acid profile reveals the important roles of several amino acids in embryo quality in patients with polycystic ovary syndrome.
X-linked transcriptome dysregulation across immune cells in systemic lupus erythematosus.
From gut to gamete: how the microbiome influences fertility and preconception health.
Inflammatory mechanisms and therapeutic advances in chronic endometritis.
H3K27me3 chromatin heterogeneity reveals variable cell responses to estrogen and endocrine treatment.
Preclinical and first-in-human evaluation of novel androgen receptor-targeted PET imaging in prostate cancer.
Recurrent pregnancy loss: Crosstalk between immune cells, decidual cells, and cellular autophagy.
Decoding Microbiome's Role in Prostate Cancer Progression and Treatment Response.
Metabolic safety of gender-affirming hormonal treatment in transgender females.
Increased Levels of Oxidative Stress in Human Prostate Intraepithelial Neoplasia and Prostate Cancer: Evidence from 4-Hydroxyneonal Detection and Its Implications.
Nasal Staphylococcus aureus carriage promotes depressive behaviour in mice via sex hormone degradation.
Identification of Adeno-Associate Virus (AAV) Serotype for Endometriosis Therapy and Effect of AAV-Mediated RNAi Delivery on Gene Expression and Cell Proliferation in In Vitro Endometrial Cell Culture.
Effects of 17β-Estradiol Treatment on Metabolic Function and Aortic Relaxation in Castrated Male Rats.
Tissue-resident memory CD8+ T cells: master deciphers of the hepatic environment.
FTO regulates testosterone secretion in Leydig cells: insights into the role of m6A modifications and the therapeutic potential of hCG.
The role of cell death pathways in respiratory viral infection and vaccination: two sides of the same coin.
Vaginal Microbiome and Its Relationship with Assisted Reproduction: A Systematic Review and Meta-Analysis.
Host-mediated selection drives sexual dimorphism of microbiota assembly in the dioecious living fossil Ginkgo biloba.
The NLRP3 inflammasome in platelets - form, functions, and future of the complex.
Comparative single-cell and spatial profiling of anti-SSA-positive and anti-centromere-positive Sjögren's disease reveals common and distinct immune activation and fibroblast-mediated inflammation.
Decoding neutrophil extracellular traps and key gene drivers in unexplained pregnancy loss.
Microbiome in heritage: how maternal microbiome transmission impacts next generation health.

Blood Adv. 2025 Sep 24. pii: bloodadvances.2024012639. [Epub ahead of print]

Androgen receptor signaling as a new target for intervention in acute myeloid leukemia.

Fenghua Qian, Deborpita Sarkar, Brooke E Arner, Vanessa M Peduzzi, Yuting Bai, Baiye Ruan, Bei Jia, Hong Zheng, Robert F Paulson, K Sandeep Prabhu.

In addition to their role in development, sex hormones and their cognate receptors play an important role in various malignancies. Using a murine model of human MLL-AF9 induced acute myeloid leukemia (AML), we discovered that high Androgen receptor (AR) expressing leukemia initiating cells (LICs) when transferred into either male or female recipients resulted in more severe disease than low AR-expressing LICs. AR expression was significantly increased in female LICs compared to male LICs. This difference was confined to the LICs and not present in normal bone marrow cells. AML cells from both sexes relied on AR signaling via different mechanisms-females had high AR with low ligand, males, low AR with high ligand. AR expression was linked to EPHA7-associated PI3K/AKT/MTOR and SRC/HIF-1α pathways. Use of the two US FDA approved drugs for prostate cancer, ARN509, an AR antagonist and finasteride, which inhibits the pathway that produces dihydrotestosterone, resulted in significant remission with increased survival of AML mice. ARN509 and finasteride also showed pro-apoptotic effect in patient-derived AML cells and in a humanized AML model in NSG mice. These data support a drug repurpose effort to use anti-androgen therapy to improve the efficacy of AML treatments.

DOI: https://doi.org/10.1182/bloodadvances.2024012639
Pediatr Res. 2025 Sep 24.

Sex differences in preterm cytokine and inflammasome responses and modulation by exogenous sex steroids.

Matthew McGovern, Lynne A Kelly, Rebecca Finnegan, John F Murphy, John Kelleher, Ashanty M Melo, Catherine M Greene, Eleanor J Molloy.

BACKGROUND: Preterm infants are at increased risk of sepsis compared to adults and older children. Preterm immune cells have altered cytokine responses compared to term neonates and adults and all have sex-related differences in immunity. We examined inflammasome activation and cytokines with endotoxin and sex steroid hormones between preterm and term neonates.
METHODS: Preterm (n = 40) and term (n = 32) peripheral blood samples were incubated with Lipopolysaccharide (LPS), Estradiol (E2), Progesterone (Pg) or Pam3CSK4 and biomarkers were analysed by ELISA. Inflammasome genes, NLR family pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein (ASC), Interleukin-1 beta (IL1-β) and Absent In Melanoma 2 (AIM 2) were analysed with Taqman RT-PCR.
RESULTS: IL-1β cytokine expression was reduced by female sex hormones and notably the effect of estradiol was greatest in the preterm population. Female preterm neonates were more responsive to the anti-inflammatory effect of progesterone than male preterm infants. Term neonates had higher IL-1β, IL-18 and IL-1RA expression than preterm infants. Overall, in preterms, E2 and Pg lowered cytokine expression levels. Inflammasome gene expression profiles did not differ between preterm male and female neonates.
CONCLUSION: Sex hormones altered the expression of multiple cytokines, and cytokine responses differ by sex. Gestation plays an important role in the inflammatory response, and we note term infants have a more robust profile while preterm infants are more responsive to hormonal stimulus. Female sex hormones have an important role in modulating neonatal immune response and may contribute to the female immune advantage.
IMPACT: Female sex hormones play an important role in modulating the neonatal immune response. This is reflected clinically by better bacterial clearance and improved sepsis outcome in females. This study aims to test the hypothesis that male and female neonates differ in their cytokine and inflammasome response and in response to endotoxin and sex steroid hormones. In preterm infants there is a sex difference in IL-1b responses which is observed rapidly following endotoxin stimulation. Differing immune responses according to sex has implications for future clinical application. Further work to characterise these sex differences may help in guiding therapy during sepsis.

DOI: https://doi.org/10.1038/s41390-025-04350-0
Int J Mol Sci. 2025 Sep 15. pii: 8976. [Epub ahead of print]26(18):

Sex Steroids in COVID-19 Patients with Hypertension: An Exploratory Study.

Pavitra Kotini-Shah, Shaveta Khosla, Felipe Borges Almeida, Luca Spiro Santovito, Heather Prendergast, Graziano Pinna.

  Sex and gender disparities have emerged as critical determinants of COVID-19 outcomes, with males exhibiting higher hospitalization and mortality rates than females. Sex steroids such as estradiol, progesterone, and testosterone have been proposed as modulators of these differences, given their known roles in inflammation, immune function, and vascular health. However, the precise hormonal mechanisms underlying COVID-19 severity, particularly among individuals with comorbid hypertension-a major risk factor for adverse outcomes-remain unclear. In this study, we investigated circulating levels of key sex hormones and their neuroactive metabolites in 116 hypertensive COVID-19 patients enrolled through an urban academic emergency department. Our findings revealed distinct sex-based hormonal profiles and associations with disease severity. Males exhibited higher serum estradiol and testosterone levels, while progesterone levels were significantly higher in postmenopausal females. Notably, hospitalized patients showed elevated estradiol and progesterone levels compared to non-hospitalized individuals, whereas ICU-admitted patients had significantly lower concentrations of all three hormones. A unique exception was ICU-admitted postmenopausal females, who exhibited increased serum testosterone levels relative to non-ICU females. Additionally, in males, elevated 3α-diol was associated with hospitalization and ICU admission, while lower allopregnanolone and estradiol levels correlated with hypoxia in males and females, respectively. These results highlight a dynamic, sex-specific hormonal response to COVID-19 progression in hypertensive individuals, suggesting early upregulation and late depletion of protective sex steroids. Understanding these patterns may improve clinical risk stratification and inform the development of sex-targeted therapeutic interventions for COVID-19 and related inflammatory conditions.

Keywords:  COVID-19; emergency department; estradiol; hypertension; neuroactive steroids; progesterone; sex steroids; testosterone

DOI:  https://doi.org/10.3390/ijms26188976
Genes (Basel). 2025 Sep 17. pii: 1101. [Epub ahead of print]16(9):

Molecular Signatures of Obesity-Associated Infertility in Polycystic Ovary Syndrome: The Emerging Role of Exosomal microRNAs and Non-Coding RNAs.

Charalampos Voros, Georgios Papadimas, Despoina Mavrogianni, Aristotelis-Marios Koulakmanidis, Diamantis Athanasiou, Kyriakos Bananis, Antonia Athanasiou, Aikaterini Athanasiou, Ioannis Papapanagiotou, Dimitrios Vaitsis, Charalampos Tsimpoukelis, Maria Anastasia Daskalaki, Vasileios Topalis, Marianna Theodora, Nikolaos Thomakos, Fotios Chatzinikolaou, Panagiotis Antsaklis, Dimitrios Loutradis, Evangelos Menenakos, Georgios Daskalakis.

  Polycystic ovarian syndrome (PCOS) is one of the most common endocrine and metabolic conditions affecting women of reproductive age. This condition affects around 20% of this demographic and is characterized by polycystic ovarian morphology, hyperandrogenism, and chronic anovulation. Obesity, impacting 40-85% of women with PCOS, exacerbates insulin resistance, increases insulin levels, and intensifies low-grade inflammation. This exacerbates the reproductive and metabolic complications associated with the condition. Recent advancements in molecular biology have underscored the significance of non-coding RNAs, including as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), as crucial regulators of gene expression and prospective biomarkers for PCOS. Exosome-derived microRNAs (ex-miRNAs) have emerged as compelling candidates due to their stability in body fluids and their capacity to promote intercellular communication among adipose tissue, the ovary, and the endometrium. Research, encompassing both experimental and clinical studies, has shown that ex-miRNAs display differing expression levels in women with obesity-related PCOS. Several of these ex-miRNAs are associated with networks that govern inflammation, glucose metabolism, steroidogenesis, and folliculogenesis. Moreover, the encapsulation of these chemicals within exosomes safeguards them from enzymatic breakdown, hence augmenting their potential as non-invasive biomarkers for diagnosis, prognosis, and treatment monitoring. Despite the initial results being encouraging, challenges remain in standardising exosome separation, quantifying miRNA, and analyzing functional data within the complex pathophysiology of PCOS. This narrative review consolidates existing evidence regarding the molecular signatures of obesity-related infertility in PCOS, emphasising the growing significance of exosomal miRNAs and other non-coding RNAs, while examining their translational potential for early diagnosis and personalised therapeutic approaches.

Keywords:  PCOS; biomarker; exosomal microRNA; folliculogenesis; infertility; insulin resistance; non-coding RNA; obesity; polycystic ovary syndrome; reproductive endocrinology

DOI:  https://doi.org/10.3390/genes16091101
Antibodies (Basel). 2025 Sep 05. pii: 76. [Epub ahead of print]14(3):

Infertility and Auto-Antibodies: A Review.

Brigita Šemeklienė, Brigita Gradauskienė.

  Infertility is a multifactorial condition with a wide range of potential causes, including anatomical, hormonal, genetic, and lifestyle-related factors. Among these, immunological mechanisms have increasingly been recognized as important contributors. The immune system plays a critical role in maintaining reproductive health, and its dysregulation can impair fertility in both men and women. Recent scientific studies suggest that altered immune responses, particularly those involving autoimmune reactions, may negatively affect fertility by disrupting the complex immunological balance required for successful conception and pregnancy maintenance. This review focuses on the most common autoantibodies, such as antinuclear, antisperm, antiendometrial, antiovarian, antiphospholipid, and antithyroid antibodies. Treatment options, including immunomodulatory therapy, hormone replacement therapy, and lifestyle interventions, are also reviewed.

Keywords:  antibodies; autoimmunity; immune cells; infertility

DOI:  https://doi.org/10.3390/antib14030076
Front Med (Lausanne). 2025 ;12 1589193

The relationship between initial vitamin D levels and in vitro fertilization (IVF) outcomes in PCOS patients: a systematic review.

Leony Octavia, Dwi Andhika Panjarwanto, Putri Nabila, Putri Lenggo Geany, R Mohamad Javier, Aldo Aulia Rahman, Vallexa Septina Yora, Lucky Sutanto, Arthur Peter Tandayu, Srigita Varsha, Sofyan Solichin.

   Background: Polycystic Ovary Syndrome (PCOS) is a common endocrine disorder affecting reproductive-age women and is often associated with infertility challenges. Recent studies suggest that vitamin D levels play a significant role in reproductive outcomes, particularly in PCOS patients undergoing in vitro fertilization (IVF).
Methods: A systematic review was conducted following PRISMA guidelines. Studies published between 2014 and 2024 were analyzed, focusing on the impact of pre-treatment vitamin D levels on IVF outcomes such as fertilization rates, implantation rates, clinical pregnancy, and live birth rates. Only studies on PCOS-related infertility were included, while non-PCOS infertility cases were excluded.
Result: The review examined 59 studies, highlighting variations in outcomes based on study design and populations. Evidence generally supports the hypothesis that adequate vitamin D levels are associated with improved IVF success, though inconsistencies remain. Further research is recommended to standardize supplementation protocols and better understand vitamin D's biological mechanisms in reproductive health.
Conclusion: The relationship between initial vitamin D levels and in vitro fertilization (IVF) outcomes in women with polycystic ovary syndrome (PCOS) suggests that vitamin D plays a crucial role in enhancing IVF success, although the findings remain somewhat inconsistent. Research generally points to a positive correlation between higher baseline vitamin D levels and improved reproductive results, including increased live birth rates, pregnancy rates, and better ovarian responses during IVF treatments.
Systematic review registration: CRD42024622381, https://www.crd.york.ac.uk/PROSPERO/view/CRD42024622381.

Keywords:  in vitro fertilization; polycystic ovary syndrome; reproductive outcomes; systematic review; vitamin D

DOI:  https://doi.org/10.3389/fmed.2025.1589193
Reprod Biol Endocrinol. 2025 Sep 24. 23(1): 123

Alteration of the follicular fluid amino acid profile reveals the important roles of several amino acids in embryo quality in patients with polycystic ovary syndrome.

Li Yu, Wei Cai, Chen Wang, Minna Shen, Miao Liu, Qi Che, Shuo Li, Xuan Zhang, Dan Shen, Yongning Lu, Xiaowei Ji, Xi Dong, Baishen Pan, Beili Wang, Suying Liu, Wei Guo.

   BACKGROUND: Polycystic ovary syndrome (PCOS) is widely acknowledged as the prevailing reproductive endocrine disorder accompanied by numerous metabolic dysfunctions. However, there has been a lack of systematic examination regarding the amino acids profile in PCOS. There is a dearth of evidence in regard to the examination of connections between amino acid metabolites found in follicular fluid (FF) and the quality of embryos during in vitro fertilization (IVF).
OBJECTIVE: Our objective was to assess amino acid signatures associated with PCOS, as well as identify potential amino acid markers for evaluating embryo quality in PCOS.
METHODS: The cohort study consisted of 143 women who were undergoing lVF/ICSl. Among these, 79 patients who had been diagnosed with PCOS, while the remaining 64 patients did not have PCOS. The concentrations of 30 amino acids present in FF were accurately determined through the use of high-performance liquid chromatography-tandem mass spectrometry. We use the spearman correlation was used to calculate correlations. Odds ratio (ORs) and 95% CIs between differential metabolites and embryo mass were estimated by the logistic regression.
RESULTS: The concentrations of glutamine (p = 0.025), taurine (p = 0.017), phenylalanine (p = 0.006), arginine (p = 0.002), histidine (p = 0.001), serine (p = 0.001), Tryptophan (p = 0.037), citrulline (p = 0.05), lysine (p = 0.012), sarcosine (p = 0.028) and 1-Methylhistidine (p = 0.006) in the PCOS group were significantly lower than those in the control group. Both PCOS and control groups showed distinct amino acid profiles between quality subgroups: in PCOS, taurine, aspartic acid, and threonine were higher in the top-quality subgroup, while in controls, alanine, glutamic acid, tyrosine, tryptophan, glycine, ornithine, threonine, and methionine were lower in the poor-quality subgroup. Lower amino acid concentrations were associated with a lower probability of high-quality embryos from IVF. We also identified 11 and 3 amino acids that related to embryo quality in the control and PCOS groups respectively.
CONCLUSION: Our research has the potential to provide valuable insights regarding the involvement of amino acid abnormalities in follicular fluid in the pathophysiology of PCOS. The findings indicated the possibility of variations in amino acid composition, and consequently variations in embryo quality, among normal and PCOS women. Additional research is required in order to substantiate these findings and directly assess the effects on pregnancy and live birth outcomes.

Keywords:  Amino acids; Embryo quality; Follicular fluid; Polycystic ovary syndrome

DOI:  https://doi.org/10.1186/s12958-025-01460-6
Biol Sex Differ. 2025 Sep 25. 16(1): 69

X-linked transcriptome dysregulation across immune cells in systemic lupus erythematosus.

Mafalda Soares, Inês Saraiva Wemans, Paulo Caldas, Simão Teixeira da Rocha, Ana Rita Grosso.

BACKGROUND: Systemic lupus erythematosus (SLE) is a complex immune-mediated disease with a strong female predominance. This sex bias may be linked to the presence of two X chromosomes, which are not always adequately dosage compensated by X chromosome inactivation (XCI). Disruption in X-linked transcriptome expression may contribute to altered immune function and increased susceptibility to autoimmunity.
METHODS: To investigate the role of X-linked gene expression in SLE, we performed a comprehensive transcriptome analysis of 27 immune cell types from 125 female SLE patients and 66 healthy controls. We further applied a multivariate approach to integrate X-linked gene expression across all immune cell types and classify SLE patients. Additionally, we extended these models to other chromosomes and explored the correlation between autosome disease markers, including members of the XIST-interactome, and X-linked expression.
RESULTS: We observed a significant increase in X-linked gene expression in T cells, B cells and plasmablasts, while monocytes and plasmacytoid dendritic cells exhibited the opposite trend. Multivariate models based solely on X-linked expression were highly accurate and highlighted key disease-associated markers. Interestingly, autosome-based models relied on markers highly correlated with X-linked gene expression and components of the XIST-interactome, which regulates XCI. Notably, we found that XIST lncRNA was consistently downregulated across multiple cell types, particularly in monocytes and Th1 cells. Such downregulation correlated with increased expression of SLE-associated genes, interferon signalling, and epigenetic regulators like KMT2D. Further analysis revealed extensive dysregulation of the XIST-interactome in SLE, predicting X-linked transcriptome alterations in a cell-type-specific manner.
CONCLUSIONS: Here, we present a comprehensive analysis of X-linked gene expression across immune cells in SLE. Our study highlights the complexity of X-linked transcriptional changes, with distinct patterns observed across both innate and adaptive immune cell types. These findings offer novel insights into the role of the X-transcriptome in sex-biased autoimmune susceptibility and may support future efforts to identify molecular targets relevant to SLE pathogenesis.

DOI: https://doi.org/10.1186/s13293-025-00750-3
Microbiome. 2025 Sep 26. 13(1): 195

From gut to gamete: how the microbiome influences fertility and preconception health.

Sarah K Munyoki, Natalie Vukmer, Julie M Rios, Amanda Kallen, Eldin Jašarević.

Global fertility rates continue to decline despite advancements in assisted reproductive technologies, highlighting a significant gap in our understanding of the mechanisms underlying preconception physiology. In this commentary, we review a growing body of work demonstrating that the microbiome plays a crucial yet underexplored role in women's reproductive health. This work has shown that microbial communities produce substrates that support metabolic, immune, and hormonal functions during this critical period, affecting fertility, pregnancy outcomes, and offspring health. Women with reproductive disorders, including endometriosis, polycystic ovarian syndrome, primary ovarian insufficiency, and recurrent pregnancy loss, harbor distinct microbial signatures. Animal studies provide key mechanistic insights, showing that disruption of microbiota accelerates ovarian aging, but translating these findings to human preconception health requires careful consideration. While these findings are compelling, this emerging field currently lacks a clear understanding of how microbial signals affect reproductive tissues through metabolites, immune responses, or hormonal pathways. We outline criteria for establishing microbial causation in preconception health, including sufficiency, necessity, specificity, and timing. Moving beyond correlations involves selecting appropriate models, focusing on key developmental windows, conducting longitudinal studies before conception, and investigating how specific microbial metabolites influence reproductive outcomes. Incorporating microbiome research into preconception care could lead to the development of new therapies and interventions. While the principles outlined here primarily address preconception reproductive health, they also offer a framework for microbiome research in general, emphasizing the need for a mechanistic understanding, timely interventions, and progress from association to causation in this rapidly evolving field.

DOI: https://doi.org/10.1186/s40168-025-02230-7
Front Immunol. 2025 ;16 1616217

Inflammatory mechanisms and therapeutic advances in chronic endometritis.

Xinyang Yan, Jiao Jiao, Xiuxia Wang.

  Chronic endometritis (CE) is a persistent inflammatory disorder of the endometrium, associated with infertility, recurrent pregnancy loss, and implantation failure. Diagnosis primarily depends on hysteroscopy and immunohistochemistry, while microbial dysbiosis and antibiotic resistance pose significant challenges to effective management. The pathogenesis of CE involves microbial infections that induce immune dysregulation through TLR/NLR signaling pathways, metabolic reprogramming of immune cells, miRNA-mediated inflammatory responses, and DNA methylation alterations. The activation of pro-inflammatory mediators and the NLRP3 inflammasome further aggravates endometrial dysfunction. Treatment typically includes oral antibiotics and intrauterine therapies, although their efficacy is variable. Probiotics have demonstrated potential in restoring microbial balance. This review outlines the inflammatory mechanisms underlying CE and recent therapeutic advancements, highlighting potential targets for improving treatment outcomes.

Keywords:  DNA methylation; NLRP3 inflammasome; TLR/NF-κB pathway; antibiotic resistance; chronic endometritis; endometrial microbiome

DOI:  https://doi.org/10.3389/fimmu.2025.1616217
bioRxiv. 2025 Sep 20. pii: 2025.09.18.677184. [Epub ahead of print]

H3K27me3 chromatin heterogeneity reveals variable cell responses to estrogen and endocrine treatment.

Chapus Fleur, Christopher R Day, Laura G Kammel, Pelin Yasar, Brian Bennett, Erica Scappini, Charles J Tucker, Maria Sifre, Celyn Bregio, Joseph Rodriguez.

Gene expression heterogeneity generates subpopulations of tumor cells that can evade therapeutic pressure. This heterogeneity has been observed in both primary Estrogen Receptor alpha positive (ERα+) breast tumors and cell lines. Therefore, understanding the mechanisms regulating expression heterogeneity is critical towards developing effective therapies. A key contributor to gene expression variability is the stochastic nature of transcription. Transcription occurs in a probabilistic, burst-like manner, in which gene activation occurs intermittently, producing RNA in pulses and interspersed with transcriptional off-periods. The estrogen-responsive gene TFF1 is expressed in the majority of ERα⁺ breast tumors and exemplifies such heterogeneity, with transcriptional inactivity ranging from minutes to several days. Here, we identify the molecular mechanism underlying the wide range in TFF1 expression by analyzing cells sorted based on their TFF1 activity levels. We observed that TFF1 inactive (TFF1low) cells exhibit a repressive chromatin state marked by H3K27me3 at the TFF1 promoter and enhancer. Despite global similarity in ERα binding, occupancy at the TFF1 regulatory elements was selectively reduced in TFF1low cells, resulting in fewer active alleles and diminished transcriptional bursting frequency. Conversely, TFF1high cells exhibited more active TFF1 alleles and hyperbursting. These cells also retained sensitivity to endocrine therapy, while TFF1low cells displayed reduced drug responsiveness. Genome-wide, differentially enriched H3K27me3 regions correlated with variable expression of estrogen-responsive genes, highlighting a broader regulatory mechanism that links chromatin state to expression variability. Together, our findings establish how repressive chromatin dynamics contribute to gene expression heterogeneity and endocrine resistance in ERα⁺ breast cancer.

DOI: https://doi.org/10.1101/2025.09.18.677184
Eur J Nucl Med Mol Imaging. 2025 Sep 23.

Preclinical and first-in-human evaluation of novel androgen receptor-targeted PET imaging in prostate cancer.

Shuyi Lin, Xiangwei Wang, Fangning Wan, Jianping Zhang, Xiaoping Xu, Bingxin Gu, Zhongyi Yang, Shaoli Song.

   PURPOSE: Activation of androgen receptor (AR) signaling is a hallmark of prostate cancer. Dynamic changes in AR expression exacerbate AR heterogeneity throughout prostate cancer therapy. This study aims to develop a series of 68Ga-labeled Enzalutamide-based positron emission tomography (PET) tracers for AR imaging.
METHODS: [68Ga]Ga-DOTA-FZAR-1, [68Ga]Ga-DOTA-FZAR-2, and [68Ga]Ga-DOTAGA-FZAR-3 were synthesized and the stability was analyzed in vitro. The AR specificity of the three radiotracers was assessed in vitro using AR-negative and AR-positive prostate cancer cell lines and in vivo using tumor xenograft-bearing mice. Moreover, the first-in-human evaluation of [68Ga]Ga-DOTA-FZAR-2 was conducted in eight patients with prostate cancer.
RESULTS: [68Ga]Ga-DOTA-FZAR-1, [68Ga]Ga-DOTA-FZAR-2, and [68Ga]Ga-DOTAGA-FZAR-3 were successfully synthesized with a radiochemical purity of more than 99%, and had good stability in vitro. Cellular uptake assays revealed that the radiotracers had the highest, intermediate, and lowest uptake in LNCaP, 22Rv1, and PC-3 cells, respectively, strongly correlating with AR expression levels (P < 0.001). Consistent with cellular uptake, the radiotracers also exhibited a hierarchical uptake pattern (highest to lowest) in tumors of mice bearing LNCaP, 22Rv1 and PC-3 xenografts, respectively. In addition, all three radiotracers were primarily eliminated through the urinary system, as confirmed by ex vivo biodistribution studies. More importantly, first-in-human investigation showed safety and diagnostic value of [68Ga]Ga-DOTA-FZAR-2 in AR-associated prostate cancer patients.
CONCLUSION: We developed and validated a series of 68Ga-labeled Enzalutamide-based PET tracers for AR imaging. Initial preclinical and clinical evidence indicate that [68Ga]Ga-DOTA-FZAR-2 enables noninvasive, whole-body, and dynamic monitoring of AR expression in prostate cancer patients throughout therapy.

Keywords:  Androgen receptor; First-in-human; Gallium-68; PET; Prostate cancer

DOI:  https://doi.org/10.1007/s00259-025-07577-5
Reprod Biol. 2025 Sep 19. pii: S1642-431X(25)00090-7. [Epub ahead of print]25(4): 101083

Recurrent pregnancy loss: Crosstalk between immune cells, decidual cells, and cellular autophagy.

Xingxing Yuan, Chaofan Li, Xiaoyu Zhang, Xiaoling Feng.

  Recurrent pregnancy loss (RPL), affecting ∼5 % of couples, remains idiopathic in up to 50 % of cases. This review synthesizes the multifactorial pathogenesis of RPL, emphasizing dysregulated molecular pathways, genetic polymorphisms such as NOS2 rs2779249, and environmental triggers such as Toxoplasma gondii infection and pesticide exposure. Immune dysfunction is central, characterized by altered Treg subsets such as reduced CD4⁺ and increased CD8⁺ Tregs, impaired checkpoint expression such as PD-1/PD-L1 and Tim-3, aberrant cytokine profiles such as elevated IL-7, IL-1β, TNF-α and reduced TGF-β, and decidual NK (dNK) cell dysregulation impacting trophoblast invasion via pathways like IGF-2/PEG10. Non-coding RNAs further contribute by promoting trophoblast apoptosis, suppressing migration/invasion, and driving inflammation through MAPK/JNK/NF-κB signaling. Decidualization defects involve metabolic imbalance, unresolved endoplasmic reticulum stress, microRNA dysregulation, TNFα-induced senescence, and disrupted β-catenin/STAT3 crosstalk. Autophagy exhibits dual role: while protective in decidual stromal cells (DSCs) by supporting Treg expansion and immune tolerance, its dysregulation triggers trophoblast apoptosis via MCL-1 degradation and caspase activation. Environmental toxins exacerbate oxidative stress and apoptosis. Therapeutic prospects include immune checkpoint agonists, lncRNA/miRNA antagonists, autophagy flux modulators, growth factor therapies, and LMWH targeting thrombotic and inflammatory pathways. However, clinical translation faces challenges, including pathway duality, pleiotropic effects, targeted delivery limitations, and limited human trial data. Future research should focus on single-cell resolution studies, personalized approaches, and safer nanocarriers for biologics to bridge mechanistic insights into effective RPL interventions.

Keywords:  Cellular autophagy; Decidual cells; Immune cells; Recurrent pregnancy loss; Therapy

DOI:  https://doi.org/10.1016/j.repbio.2025.101083
Diseases. 2025 Sep 05. pii: 294. [Epub ahead of print]13(9):

Decoding Microbiome's Role in Prostate Cancer Progression and Treatment Response.

Minas Sakellakis, Panagiota Resta, Evangelia Papagianni, Kassandra A Procter, Irene Belouka, Katerina Gioti, Fragkiski Anthouli-Anagnostopoulou, Dimitrios Chaniotis, Apostolos Beloukas.

  Prostate cancer (PCa) is the most common genitourinary malignancy in men, with a multifactorial etiology influenced by genetic, environmental, and microbial determinants. Although the prostate was traditionally considered sterile, advances in microbiome research have challenged this view, revealing potential links between microbial communities and PCa development, progression, and treatment response. This review synthesizes evidence on the gut, urinary, seminal fluid, and prostatic microbiomes, highlighting their potential contributions to PCa pathogenesis and therapeutic outcomes. Key studies utilizing next-generation sequencing (NGS), whole-genome sequencing (WGS), PCR, and metagenomic analyses have identified specific bacterial and fungal taxa associated with Pca; however, findings remain inconsistent across methodologies and cohorts. Microorganisms such as Propionibacterium acnes and Pseudomonas spp. may modulate inflammation, immune responses, and resistance to androgen-deprivation therapy. Further research is required to determine whether microbial signatures can serve as reliable biomarkers for early detection, prognosis, or novel therapeutic strategies in PCa management.

Keywords:  gut microbiome; microbial biomarker; microbiota; next-generation sequencing; prostate cancer

DOI:  https://doi.org/10.3390/diseases13090294
Sex Health. 2025 Aug;pii: SH25113. [Epub ahead of print]22

Metabolic safety of gender-affirming hormonal treatment in transgender females.

Charalampos Milionis, Konstantina Barouti, Vassiliki Papadopoulou, Foteini Pouliasi, Efthymia Karlafti, Sofia Makrydima, Stavroula Karampa, Evaggelia Venaki, Eftychia Koukkou.

Background Gender incongruence results from the mismatch between gender identity and thesex assigned at birth. The process of gender affirmation includes a series of procedures during which the transgender individual acquires phenotypic features of the desired sex. Hormonal therapy for transgender women aims to suppress endogenous androgens and replace them with estrogens. The present study sought to investigate the safety of feminizing therapy in transgender women in relation to somatometric and metabolic parameters. Methods The medical records of transgender women who received oral estradiol valerate and a gonadotropin-releasing hormone (GnRH) agonist for at least 18months were reviewed. The study population had estradiol levels within the normal limits of the follicular phase of cisgender women of reproductive age and suppressed blood testosterone levels after 18months of treatment. Changes in body mass index, glycemic and lipid profiles, hemoglobin and hematocrit, and liver function tests were examined. The paired t -test was used for statistical analysis. Results The mean blood estradiol and testosterone levels after approximately 18months of treatment were 85.65pg/mL and 24ng/dL, respectively. There was a statistically significant increase in blood triglycerides as well as a statistically significant decrease in hemoglobin and hematocrit. However, none of the participants developed severe hypertriglyceridemia or anemia. No significant changes were found in blood cholesterol (total, high-density lipoprotein, and low-density lipoprotein cholesterol), glucose, and liver enzymes. Conclusions Treatment with oral estradiol valerate and an intramuscular GnRH agonist is used in daily clinical practice to promote feminizing physical changes in transgender women. However, the possibility of side effects is not well documented. The present study demonstrated that achieving estradiol and testosterone levels within therapeutic targets is important for the safety of gender-affirming therapy.

DOI: https://doi.org/10.1071/SH25113
Antioxidants (Basel). 2025 Aug 28. pii: 1060. [Epub ahead of print]14(9):

Increased Levels of Oxidative Stress in Human Prostate Intraepithelial Neoplasia and Prostate Cancer: Evidence from 4-Hydroxyneonal Detection and Its Implications.

Geou-Yarh Liou, Woojung Kim, Tamiya M Hobbs.

  Prostate cancer is not only the most common type of cancer in elderly American men but also the 2nd leading cause of cancer death in American men. The currently available treatments in clinics target male hormones that are majorly required for maintaining many physiological functions, including muscle strength, leading to poor life quality and subsequent patient-opted intermittent treatment. Aging is a key factor in prostate cancer that is associated with increased levels of oxidative stress. Several lines of evidence indicated elevated levels of reactive oxygen species (ROS) in prostate cancer, including its precursor, prostate intraepithelial neoplasia (PIN). In this current study, we utilized 4-hydroxynonenal (4HNE) as a general readout for overall oxidative stress to demonstrate the imbalance between ROS and antioxidants in human prostate cancer and its precursor lesion in both human culture cell lines and tissue samples. Our results showed that the production of 4HNE adducts was increased in human prostate cancer cells and was non-linearly correlated with prostate cancer stage. They also provided insight into prevention and potential therapeutic strategies for prostate cancer.

Keywords:  4HNE protein adducts; inflammation; oxidative stress; prostate cancer; prostate intraepithelial neoplasia; reactive oxygen species

DOI:  https://doi.org/10.3390/antiox14091060
Nat Microbiol. 2025 Sep 22.

Nasal Staphylococcus aureus carriage promotes depressive behaviour in mice via sex hormone degradation.

Guoxiu Xiang, Yanan Wang, Kaiji Ni, Huoqing Luo, Qian Liu, Yan Song, Ping Miao, Lei He, Ying Jian, Ziyu Yang, Tianchi Chen, Ke Xu, Xia Sun, Zhen Shen, Chenfeng Ji, Na Zhao, Mengxin He, Yan Pan, Yanli Luo, Ji Hu, Michael Otto, Min Li.

The human microbiome has a pronounced impact on human physiology and behaviour. Despite its unique anatomical connection to the brain, the role of the nasal microbiome in neurological diseases is understudied. Here, using human data and experiments in mice, we show that nasal Staphylococcus aureus is linked to depression. Nasal microbiome analyses revealed a positive correlation between depression scores and S. aureus abundance among patients with depression and healthy controls. Metabolomics of the nasal cavity showed decreased sex hormones, estradiol and testosterone in patients with depression versus controls. Nasal microbiota transplants from patients reproduced depression-like behaviour in mice with differential abundance of S. aureus. Further homology and mutational analysis uncovered an S. aureus sex hormone-degrading enzyme, 17b-hydroxysteroid dehydrogenase (Hsd12), which degraded testosterone and estradiol in mice, leading to lower levels of dopamine and serotonin in the murine brain. These findings reveal a nasal commensal that influences depressive behaviour and provides insights into the nose-brain axis.

DOI: https://doi.org/10.1038/s41564-025-02120-6
Microorganisms. 2025 Sep 13. pii: 2144. [Epub ahead of print]13(9):

Identification of Adeno-Associate Virus (AAV) Serotype for Endometriosis Therapy and Effect of AAV-Mediated RNAi Delivery on Gene Expression and Cell Proliferation in In Vitro Endometrial Cell Culture.

Jin Kyung Baek, Jaekyung Lee, Yun Soo Chung, Seokkyo Seo.

  Endometriosis is a chronic estrogen-dependent condition with limited treatment options, often requiring surgery and long-term hormonal therapy that may impair ovarian function. Despite advancements in gene therapy for other diseases, its application in endometriosis remains largely unexplored. This study aimed to evaluate the potential of adeno-associated virus (AAV) vectors for targeted gene therapy in endometriosis. We screened multiple AAV serotypes for infectivity in primary human ectopic and eutopic endometrial cells as well as normal ovarian stromal cells. AAV serotype 3 (AAV3) demonstrated selective infectivity toward endometrial cells while sparing ovarian tissue. AAV3-mediated delivery of small interfering RNA targeting estrogen receptor 2 reduced Estrogen receptor beta (ERβ) expression to 27% in ectopic and 49% in eutopic cells. Under estradiol and inflammatory stimulation, ERβ knockdown led to modest reductions in cellular metabolic activity in eutopic cells, whereas effects in ectopic cells did not reach statistical significance. Dual targeting of ERβ and prostaglandin-endoperoxide synthase 2 (PTGS2) showed numerically lower metabolic activity than controls under some conditions but without consistent statistical significances. These findings suggest that AAV3 can serve as an ovary-sparing, endometriosis-specific vector that facilitates gene silencing while yielding limited phenotypic effects. This gene delivery system may provide a basis for developing future gene-based therapies for endometriosis.

Keywords:  RNA interference; adeno-associate virus; ectopic endometrium; endometriosis; endometriosis cell culture; gene therapy

DOI:  https://doi.org/10.3390/microorganisms13092144
Int J Mol Sci. 2025 Sep 12. pii: 8885. [Epub ahead of print]26(18):

Effects of 17β-Estradiol Treatment on Metabolic Function and Aortic Relaxation in Castrated Male Rats.

Rifat Ara Islam, Md Rahatullah Razan, Ankita Poojari, Mohammad Moshiur Rahman, Hao Wei, Hana S Alhamadsheh, Melanie Felmlee, Atefeh Rabiee, Mitra Esfandiarei, Roshanak Rahimian.

  Exogenous estrogen use in male-to-female individuals has been linked to increased cardiovascular disease risk, though the mechanisms remain unclear. This study examines the effects of 17β-estradiol (E2) on metabolic and aortic function in castrated (CAS) male Sprague Dawley rats. CAS rats received subcutaneous E2 (CAS + E2) or placebo (CAS + PL) pellets for ~35 days, with intact males serving as controls. Endothelium-dependent vasorelaxation (EDV) in response to acetylcholine and contractile responses to phenylephrine were measured in aorta before and after pharmacological inhibitors. Metabolic parameters and expression of proteins associated with vascular and insulin signaling were also determined in aorta and white adipose tissue (WAT). E2 treatment reduced body weight, improved HbA1c and enhanced glucose tolerance in CAS rats compared to the CAS + PL group. Improved glucose homeostasis was associated with upregulation of estrogen receptor alpha, phosphorylated Akt/Akt, and glucose transporter-4 expression in WAT. However, E2 increased plasma triglyceride and impaired EDV, indicating compromised vascular function. Our results suggest that impaired aortic relaxation in the CAS + E2 group may be partly attributable to increased contractility. Additionally, we observed reduced G protein-coupled estrogen receptor and elevated inducible nitric oxide synthase expression, warranting further investigation into whether these factors contribute to the effects of E2 on aortic relaxation.

Keywords:  Cardiovascular disease; aortic relaxation; estrogen-treatment; male-to-female; nitric oxide (NO)

DOI:  https://doi.org/10.3390/ijms26188885
Nat Rev Gastroenterol Hepatol. 2025 Sep 22.

Tissue-resident memory CD8+ T cells: master deciphers of the hepatic environment.

Daniel Brown Romero, George E Finney, Michael Dudek, Laura J Pallett.

Tissue-resident memory CD8+ T (CD8+ TRM) cells are localized within peripheral tissues, such as the liver, poised to provide effective immunosurveillance, as well as rapid and enhanced effector functions upon stimulation. Here we review how hepatic CD8+ TRM cells decipher a myriad of environmental signals, ranging from cellular and soluble factors to direct interactions with the underlying stroma and structural tissue niche, which dictate their derivation, retention and function. We discuss insights from both mouse and human studies that have contributed to our understanding of how CD8+ TRM cells can, depending on the context, provide targeted antigen-specific antiviral and antitumour immune responses and elicit antigen-independent tissue-damaging responses that contribute to liver pathology. Specifically, we discuss how the CD8+ TRM cell functional response is shaped by multiple factors and how such environmental cues tip the balance between these dual 'Jekyll and Hyde' response modes. Finally, we examine strategies to better identify and characterize hepatic CD8⁺ TRM cells and how the enhanced functionality of CD8+ TRM cells can be harnessed therapeutically in the context of hepatocellular carcinoma.

DOI: https://doi.org/10.1038/s41575-025-01118-z
Reprod Biol Endocrinol. 2025 Sep 24. 23(1): 121

FTO regulates testosterone secretion in Leydig cells: insights into the role of m6A modifications and the therapeutic potential of hCG.

Chenglu Wang, Kebing Yang, Fang Gao, Min Zheng, Xiaohua Fu.

   BACKGROUND: Testosterone plays a pivotal role in male reproductive health and is synthesized primarily by Leydig cells (LCs) in the testes. Alterations in testosterone levels can lead to sexual dysfunction, reduced fertility, and various systemic health issues. FTO, an m6A demethylase, has been implicated in the regulation of RNA modification and has significant roles in various biological processes. However, its influence on testosterone secretion in LCs remains unclear.
OBJECTIVE: This study aims to investigate the role of FTO in regulating testosterone secretion by LCs and to explore the potential impact of hCG treatment in rescuing the effects of FTO inhibition.
METHODS: In this study, we assessed the mRNA and protein expression levels of FTO in LCs from 39 male patients diagnosed with obstructive azoospermia. Additionally, FTO knockdown was performed in TM3 cells, followed by analysis of cell proliferation, apoptosis, and testosterone secretion. The effect of hCG on rescuing FTO inhibition-induced changes was also evaluated.
RESULTS: We identified a positive correlation between FTO expression levels and testosterone concentrations in LCs from 39 male patients with obstructive azoospermia. FTO knockdown in TM3 cells significantly reduced testosterone secretion, cell proliferation, and increased apoptosis. Specifically, 48 h post-transfection, the apoptosis rate in shRNA-FTO-transfected TM3 cells was 6.26%, significantly higher than in mock-transfected cells (3.03%, P = 0.013). FTO inhibition also markedly suppressed cell proliferation by 26.2% (P < 0.0001) at 24 h, 34.3% (P = 0.0006) at 48 h, and 21.5% (P = 0.002) at 72 h, as measured by CCK-8 assay. However, the addition of 10 IU hCG significantly rescued the proliferation and reduced the apoptosis rate in the FTO knockdown group. Testosterone secretion in the FTO inhibition group was also significantly lower than in controls at all time points (6, 24, 48, and 72 h), but hCG treatment restored testosterone levels by 26.4% (P = 0.003) at 6 h, 29.4% (P = 0.0026) at 24 h, 18.8% (P = 0.028) at 48 h, and 36.6% (P = 0.0005) at 72 h.
CONCLUSION: Our study provides new evidence that FTO plays a critical role in regulating testosterone secretion in LCs. Additionally, we demonstrate that hCG treatment can restore testosterone production impaired by FTO inhibition. These findings offer valuable insights into the molecular mechanisms underlying testosterone secretion and may inform therapeutic strategies for male infertility and hypogonadism.

Keywords:  FTO; HCG; Leydig cells; M6A modification; Testosterone secretion

DOI:  https://doi.org/10.1186/s12958-025-01456-2
Front Immunol. 2025 ;16 1650960

The role of cell death pathways in respiratory viral infection and vaccination: two sides of the same coin.

Sun Min Lee, Eui Ho Kim.

  Cell death pathways play contrasting roles in physiological processes such as responses to viral infections and vaccinations, potentially exerting either detrimental or beneficial effects. On one hand, uncontrolled cell death accompanied by the release of damage-associated molecular patterns (DAMPs) can lead to excessive inflammation and tissue damage. On the other hand, when properly regulated, these processes help establish an immunocompetent environment by activating innate immunity, which in turn stimulate antiviral immune responses. These mechanisms have emerged as promising targets for the development of effective antiviral therapeutics, immunotherapies, and vaccines. Recent advances have elucidated key aspects of cell death and DAMP pathways, highlighting their association with upstream viral sensors, their capacity to regulate immune responses, and their potential as therapeutic targets in the context of respiratory viral infections such as influenza virus and SARS-CoV-2. In this review, we discuss the advantages and disadvantages of cell death and DAMP pathways, focusing on their roles in antiviral immunity and pathogenesis of respiratory viral infections, and vaccine immunogenicity.

Keywords:  adjuvants; cell death pathways; damage-associated molecular patterns (DAMPs); vaccines; viral infections

DOI:  https://doi.org/10.3389/fimmu.2025.1650960
Life (Basel). 2025 Sep 01. pii: 1382. [Epub ahead of print]15(9):

Vaginal Microbiome and Its Relationship with Assisted Reproduction: A Systematic Review and Meta-Analysis.

Marise Samama, Joji Ueno, Eduardo Carvalho de Arruda Veiga, Rita C C P Piscopo, Fabio Ikeda, Nina Pires de Lemos, Lucas Tadeu Bidinotto, Márcia Guimarães da Silva, Zsuzsanna Jarmy Di Bella, Frida Entezami.

  Background: The vaginal microbiome is an important factor influencing clinical outcomes in women undergoing assisted reproductive techniques. Objective: Our review aimed to confirm that women with a favorable vaginal microbiome have better reproductive outcomes than women who have an unfavorable vaginal microbiome. Methods: This systematic review and meta-analysis included articles published in the last 10 years, identified through keyword searches in PubMed and MEDLINE using the MeSH terms "vaginal microbiome," "reproduction," and "human reproduction." The search yielded 1735 records. Participants were categorized into women with a favorable microbiome and those with an unfavorable microbiome. To refine the taxonomic resolution at the species level, we additionally performed a bioinformatic analysis of a cohort of 56 women using multivariable association with linear models (MaAsLin2). Results: Women with a favorable microbiome had higher pregnancy rates compared to those with a less favorable microbiome (p = 0.0001, I2 = 0%, RR: 1.59). Live birth rates were also significantly higher in the favorable microbiome group than in the unfavorable microbiome group (p = 0.004, I2 = 0%, RR:1.41), with no evidence of heterogeneity. Women with an unfavorable microbiome had more miscarriages than women with a favorable microbiome (p = 0.04, I2 = 0%, RR: 0.65). Bioinformatic analysis showed that a high relative abundance of Lactobacillus crispatus increased the likelihood of pregnancy approximately sixfold. Conclusions: The favorable microbiome group, particularly participants with a high relative abundance of Lactobacillus crispatus, demonstrated better reproductive outcomes, with a higher clinical pregnancy rate, a higher live birth rate, and a lower rate of pregnancy loss, although there was a low-quality bias.

Keywords:  clinical pregnancy rate; live birth rate; pregnancy loss; systematic review; vaginal microbiome

DOI:  https://doi.org/10.3390/life15091382
New Phytol. 2025 Sep 27.

Host-mediated selection drives sexual dimorphism of microbiota assembly in the dioecious living fossil Ginkgo biloba.

Chen-Feng Lin, Jun-Jie Wu, Yun-Peng Zhao.

  Dioecious plants harbor sexually dimorphic microbiota that enhance their reproductive success. However, the spatial and temporal patterns, particularly the ecological processes underlying the sexual dimorphism of plant microbiota assembly, remain largely unknown. We investigated the bacterial and fungal communities in 180 samples collected from male and female trees of Ginkgo biloba across three niches and three developmental stages, quantifying the relative importance of host-mediated selection to assess the role of host sex in microbiota assembly. Our results revealed significant filtering of ginkgo microbiota along the soil-root-leaf continuum, as well as dynamic shifts throughout the annual growth cycle of the host. Male and female hosts exerted differential selection on specific microbial taxa, leading to sexually dimorphic microbiota compositions with spatiotemporal variations. Chemoheterotrophic bacteria were enriched in male leaves during the flowering stage, whereas pathogenic and saprotrophic fungi were depleted in female trees during the seed set stage. Host-mediated selection on specific microbial functional groups drives the sexual dimorphism of microbiota assembly, aligning with sex-specific reproductive and adaptive strategies. Our findings reveal a dynamic connection between plant sex and microbiota function in long-lived woody plants, and lay a foundation for future microbiome-assisted conservation of dioecious species.

Keywords:  Ginkgo biloba; dioecious plants; host‐mediated selection; microbiota assembly; sexual dimorphism; spatiotemporal dynamics

DOI:  https://doi.org/10.1111/nph.70591
Platelets. 2025 Dec;36(1): 2562267

The NLRP3 inflammasome in platelets - form, functions, and future of the complex.

Matthew S Hindle, Martin Berger, Khalid M Naseem.

  Platelets are anucleate cells that primarily facilitate thrombosis and hemostasis but can also act as mediators of vascular inflammation in disease. Platelets are typically understood to do this through the release of pre-formed chemokines coupled with direct heterotypic interactions with a variety of immune cells. However, an alternative mode of action has been described where platelets are able to undertake de novo synthesis of the cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18). The primary mechanism to produce these inflammatory mediators is the activation of the NACHT leucine-rich repeat pyrin domain-containing protein 3 (NLRP3) inflammasome, a multi-protein complex that processes IL-1β and IL-18 through caspase activation. The presence and characteristics of the NLRP3 inflammasome have been widely described in a variety of nucleated cells, although its role in anucleate platelets is less clear. In the last decade, the presence of the inflammasome has been reported in platelets and linked to several diseased states including sickle cell disease, acute coronary syndrome, sepsis, and viral hemorrhagic fever. This emerging new biology of platelets, its role in platelet function, vascular inflammation, and other related areas of exploration are critically reviewed here.

Keywords:  Inflammasome; NLRP3; inflammation; interleukin-1β; platelets

DOI:  https://doi.org/10.1080/09537104.2025.2562267
Nat Commun. 2025 Sep 22. 16(1): 8299

Comparative single-cell and spatial profiling of anti-SSA-positive and anti-centromere-positive Sjögren's disease reveals common and distinct immune activation and fibroblast-mediated inflammation.

Jun Inamo, Masaru Takeshita, Katsuya Suzuki, Kazuyuki Tsunoda, Satoshi Usuda, Junko Kuramoto, Jonathan Moody, Chung-Chau Hon, Yoshinari Ando, Takashi Sasaki, Kazutoshi Yoshitake, Susumu Mitsuyama, Shuichi Asakawa, Yae Kanai, Tsutomu Takeuchi, Yuko Kaneko.

Sjögren's disease (SjD) is an autoimmune disease that causes salivary gland dysfunction due to immune-mediated destruction. While autoantibodies such as anti-SSA and anti-centromere (CENT) are associated with distinct clinical manifestations, the molecular features remain to be elucidated. In this study, we apply multi-modal single-cell technologies: single-cell RNA sequencing, T cell and B cell receptor sequencing and spatial transcriptomics to salivary gland lesions, aiming to elucidate common and unique cellular and transcriptional signatures linked to different autoantibody profiles. Our analysis demonstrates that GZMB+GNLY+ CD8+ T cells are the main expanded subset across different autoantibody statuses, highlighting their central role in SjD pathogenesis, while the enrichment of memory B cells is more prominent in anti-CENT-positive patients. Cytokine signaling also differs by autoantibody profile, with an activated interferon signature in anti-SSA-positive patients, whereas TGFβ signaling is enhanced in anti-CENT-positive patients. Furthermore, spatial profiling reveals THY1+ fibroblasts, expressing complement genes and chemokines, as key hubs orchestrating inflammation within the salivary glands. These findings deepen our understanding of the pathogenesis of SjD, and may inform the development of targeted and personalized therapeutic strategies.

DOI: https://doi.org/10.1038/s41467-025-63935-9
Front Immunol. 2025 ;16 1628337

Decoding neutrophil extracellular traps and key gene drivers in unexplained pregnancy loss.

Hui Ding, Lu Zhang, Wei Yang, Yu Liu, Chao Wang, Li Liu, Cheng Li, Liyuan Pan, Lin Chen, Meimei Liu.

   Background: Recurrent pregnancy loss (RPL) represents a critical reproductive health concern, with nearly half of RPL cases lacking clinically identifiable etiologies, termed unexplained RPL (uRPL). Neutrophil extracellular traps (NETs), released by activated neutrophils, have been implicated in the pathogenesis and progression of various reproductive disorders. However, the relationship between NETs and uRPL remains poorly characterized.
Methods: This study enrolled 34 patients with uRPL and 30 healthy controls. Serum NETs biomarkers (MPO-DNA, citH3) were quantified via ELISA. Decidual tissues underwent histopathology (H&E), immunohistochemistry, and transcriptomics (6uRPL vs. 5 controls). Machine learning identified key NETs-related differentially expressed genes, validated by Western blotting. Immune cell infiltration and gene-immune correlations were assessed bioinformatically.
Results: uRPL patients exhibited elevated serum NETs biomarkers (MPO-DNA, citH3; p<0.01) and increased decidual neutrophil infiltration. Immunohistochemistry confirmed upregulated MPO and citH3 in uRPL (p<0.01). Transcriptomics identified four key DE-NRGs (C3AR1, ITGAM, ITGB2, LYZ), validated at the protein level (p<0.05). Immune profiling revealed increased CD8+ T cells, M2 macrophages, and neutrophils, alongside reduced CD4+ memory T cells, follicular helper T cells, and monocytes in uRPL. All DE-NRGs correlated positively with M2 macrophages (r>0.6) and negatively with follicular helper T cells and monocytes (r<-0.5). LYZ also correlated with neutrophils (r>0.5). A nomogram incorporating DE-NRGs demonstrated robust diagnostic accuracy (AUC>0.85).
Conclusion: This study establishes a novel link between NETs and the pathogenesis of uRPL. It highlights the abnormal activation of C3AR1, ITGAM, ITGB2, and LYZ, along with M2 macrophage polarization, as crucial factors in decidual immune dysregulation. These findings suggest that NETs could serve as therapeutic targets, while DE-NRGs may act as potential biomarkers for uRPL.

Keywords:  decidual inflammation; immune microenvironment; machine learning algorithms; neutrophil extracellular traps (NETs); unexplained recurrent pregnancy loss (uRPL)

DOI:  https://doi.org/10.3389/fimmu.2025.1628337
Microbiome. 2025 Sep 26. 13(1): 196

Microbiome in heritage: how maternal microbiome transmission impacts next generation health.

Clara Delaroque, Benoit Chassaing.

After birth, the infant's intestine is colonized by microorganisms, initiating a period of rapid microbial expansion and major compositional maturation influenced by both maternal and environmental factors. Simultaneously, the host's intestinal environment exhibits unique characteristics that facilitate critical interactions with the developing microbiome during this early-life window. These early biological events have lasting effects on health, fostering immune tolerance to environmental exposures or, conversely, increasing susceptibility to noncommunicable diseases-such as allergies, obesity, and inflammatory bowel disease-if microbiome development is disrupted. In this review, we summarize recent advances in understanding the key stages of microbiome development after birth and explore how changes in the maternal environment-especially diet-as well as maternal intestinal bacteria and their derived molecules shape the microbiome's composition and function in early-life, ultimately influencing long-term health and disease risk. Video Abstract.

DOI: https://doi.org/10.1186/s40168-025-02186-8