bims-simsho 2025-12-21 papers

bims-simsho

Biomed News

on Systems immunology and sex hormones

Issue of 2025–12–21
twenty-six papers selected by
Chun-Chi Chang, Lunds universitet

The Multifaceted Role of Androgen Receptor Signaling in Immunity: Implications for Oncology.
Sex influences murine T cell responses to vaccination with BCG or BCG∆BCG1419 grown as biofilms.
Sex Hormones Associate With Amyotrophic Lateral Sclerosis Risk and Survival.
Genetic Background and Sex Modulate Androgen Responses in Human Brain Microphysiological System.
HIV-Exposed Seronegative Female Sex Workers Show Different Cellular Immune Profiles Across the Menstrual Cycle.
Sex and reproductive condition shape thermal acclimation strategy in a plethodontid salamander.
Don't sleep on sex differences: circadian influences and considerations in sex-specific research.
The maternal-infant microbiome axis as an epigenetic and immunometabolic orchestrator: redefining early-life programming and precision interventions for lifelong women's and children's health.
Single-cell transcriptome analyses reveal disturbed decidual microenvironment in women of advanced maternal age.
Estradiol enhances B cell humoral immune responses against genital herpes simplex virus type 2 in mice through an IL-17 dependant pathway.
Hyperinflammation by Human Macrophages Induced by SARS-CoV-2 Anti-Spike IgG Is Dependent on Glucose and Fatty Acid Metabolism.
Association of female reproductive traits with altered aging trajectories: Insights from genetic and observational analyses.
Systemic and mucosal immune signatures of protection against SARS-CoV-2 transmission in humans.
Oxysterol-mediated modulation of intestinal inflammation: insights into sex differences and GPR183 signaling.
NLRP3 inflammasome activation in the placenta during SARS-CoV-2 infection.
Arginine Metabolism in Decidual Macrophages During Pregnancy.
CD27 agonism enhances long-lived CD4 T cell vaccine responses critical for antitumor immunity.
GSNOR deletion differentially alters age-related cardiac function in a sex-dependent manner.
Sexually dimorphic developmental changes in rat spinal cord pain pathways following neonatal inflammation.
Oxytocin varies across the life course in a sex-specific way in a human subsistence population.
Apocrine encapsulated papillary carcinoma: a comprehensive clinicopathological analysis of 28 cases.
[Endocrine and metabolic changes in prostate cancer patients after radical prostatectomy].
Spatiotemporal cellular map of the developing human reproductive tract.
Antibiotic use in early life impairs MAIT cell-mediated immunity in adulthood.
Long-term immune and epigenetic dysregulation following COVID-19.
Cholecystokinin (CCK) mediates CCKBR to regulate androgen secretion via the steroid pathway in Bactrian camel Sertoli cells.

Mol Cancer Res. 2025 Dec 15.

The Multifaceted Role of Androgen Receptor Signaling in Immunity: Implications for Oncology.

Patrick Lee, Peter S Nelson.

While the androgen receptor (AR) is canonically known for its role in the prostate and testis, AR signaling exerts broad immunomodulatory effects through direct and indirect signaling in multiple immune cell compartments and contributes significantly to sex differences in autoimmunity, infection, and cancer. Mouse model perturbations of androgen signaling through castration, testicular feminization, and cell type-specific AR knockout have provided important insights into cell-intrinsic and -extrinsic mechanisms by which AR signaling affects innate and adaptive immunity. However, the precise molecular underpinnings of these effects remain largely unknown. Moreover, despite convincing epidemiological and correlative observations that highlight the importance of AR signaling in human immune function, it remains unclear how reliably findings in mice will translate to humans. A better understanding of how to augment immune function through androgen signaling modulation could have significant clinical relevance for the treatment of cancer, as well as other disease states involving immune dysregulation. In this review, we discuss the current evidence for the functional effects of AR signaling within the major immune cell compartments of the innate and adaptive immune systems. We also review ongoing clinical efforts that modify AR signaling for the purpose of enhancing antitumor immunity.

DOI: https://doi.org/10.1158/1541-7786.MCR-25-0802
Mem Inst Oswaldo Cruz. 2025 ;pii: S0074-02762025000101161. [Epub ahead of print]120 e250015

Sex influences murine T cell responses to vaccination with BCG or BCG∆BCG1419 grown as biofilms.

Mario Alberto Flores-Valdez, Cristian Alfredo Segura-Cerda, César Pedroza-Roldán, Jorge Gómez-Haro, Dulce Mata-Espinosa, María Guadalupe Jorge-Espinoza.

BACKGROUND: It is known that host sex can influence the immune response to administration of Mycobacterium bovis Bacillus Calmette-Guérin (BCG). However, the effect of BCG or BCG-derived vaccines cultured as biofilms on development of T cell responses in both sexes remains unclear.
OBJECTIVES: To compare the influence of sex and vaccine strain (BCG Pasteur vs. BCGΔBCG1419c) on ex vivo T cell responses against mycobacterial purified protein derivative (PPD) stimulation in lung and spleen cells of mice vaccinated with bacteria grown as biofilms.
METHODS: Male and female BALB/c mice were subcutaneously vaccinated with disaggregated, biofilm-derived BCG Pasteur or BCGΔBCG1419c. Sixty days later, lung and spleen cells were collected and stimulated ex vivo with PPD. Flow cytometry was used to quantify frequencies of mono- and bi-functional CD4⁺ and CD8a⁺ T cells expressing interferon gamma (IFN-γ) and tumour necrosis factor alpha (TNF-α) or interleukin-2 (IL-2), as well as frequencies of tissue-resident memory CD4⁺ T cells.
FINDINGS: Sex influenced T cell responses in both organs. Lungs of female mice vaccinated with BCGΔBCG1419c showed reduced frequencies of CD8a⁺ IFN-γ⁺, and reduced frequency of CD4⁺ IFN-γ⁺ in spleen, compared with males. On the other hand, female mice vaccinated with BCG produced higher IL-2+ and IL-2+TNF-α+ T cells in spleen than paired males. Vaccine strain alone had limited effects, but sex-strain interactions shaped distinct immune profiles.
MAIN CONCLUSIONS: Sex modulates the immunogenicity of BCG-based vaccines grown as biofilms. Our results underscore the importance of considering host sex and vaccine preparation in tuberculosis preclinical research.

DOI: https://doi.org/10.1590/0074-02760250015
Ann Clin Transl Neurol. 2025 Dec 18.

Sex Hormones Associate With Amyotrophic Lateral Sclerosis Risk and Survival.

Stephen A Goutman, David G Stouffer, Dae-Gyu Jang, Jihyun Park, Benjamin J Murdock, Richard J Auchus.

  Amyotrophic lateral sclerosis (ALS) risk differs by sex and age, implicating sex hormones as potential modifiers. This study examined plasma levels of biologically active sex hormones and their association with ALS odds and survival in cases (females n = 131, males n = 189) and controls (females n = 138, males n = 150) from the University of Michigan Pranger ALS Clinic. Higher 11-ketotestosterone levels were associated with increased ALS odds. In females, higher estrone, androstenedione, and 11-hydroxyandrostenedione were associated with increased ALS odds, while elevated estrone and estradiol predicted shorter survival. These findings highlight the potential significance of sex hormones in ALS.

Keywords:  11‐hydroxyandrostenedione; 11‐keto‐; ALS; androestenedione; estradiol; estrogen; estrone; sex hormones; steroids; testosterone

DOI:  https://doi.org/10.1002/acn3.70281
bioRxiv. 2025 Dec 08. pii: 2025.12.03.692130. [Epub ahead of print]

Genetic Background and Sex Modulate Androgen Responses in Human Brain Microphysiological System.

Maren Schenke, Jason Laird, Alex Rittenhouse, Viktoriya Kucheryavenko, Winfried Neuhaus, Ou Chen, Sarven Sabunciyan, Alexandra Maertens, Lena Smirnova.

Sex steroids shape human brain development, yet the cellular and molecular consequences of androgen addition need further exploration. Here, we used a human neural organoid model - brain microphysiological system (bMPS), derived from nine induced pluripotent stem cell (iPSC) lines to model the impact of dihydrotestosterone (DHT), a potent non-aromatizable androgen. All lines differentiated reproducibly into electrically active, neuron-glia-oligodendrocyte organoids expressing robust androgen-signaling components. DHT was bioavailable, elicited nuclear androgen receptor (AR) translocation and increased organoid size in most cell lines, consistent with androgen-responsive mTOR and metabolic pathway activation. Bulk RNA-seq across nine lines revealed that transcriptional responses varied across donor backgrounds, but DHT-responsive genes converged on mitochondrial energetics, lysosomal function, glycoprotein processing, apoptosis, and mTOR signaling. Cell-type expression profiling showed an androgen-driven shift primarily in male lines toward astrocytic profiles with reductions in oligodendrocyte, oligodendrocyte progenitor (OPC), excitatory, and inhibitory neuronal signatures, supported by immunohistochemistry and AR enrichment in astrocytes and OPCs. DHT also altered neurodevelopmental pathways, increasing variation in synaptic pruning and decreasing variation in neuronal migration, with autism spectrum disorder (ASD) diagnosis and seizure status of donors moderating these effects more strongly than sex. Baseline transcriptional differences distinguished iPSC lines which responded more strongly to DHT from weak responders: responders displayed enhanced synaptic maturity and reduced ECM gene expression. Using isogenic XX/XY lines, we found that differences in sex-chromosome expression exceeded DHT-induced changes and that DHT decreased expression of inhibitory neuron genes in males and increased it in females. Finally, DHT induced extensive DNA methylation changes, targeting HOX genes, patterning, and synaptic genes. Collectively, these findings reveal that androgen signaling shapes transcription, cell populations, and epigenetic landscapes in a genetic background-dependent manner. This work contributes to understanding how androgens influence human brain development and highlights how in vitro models can contribute to representing inter-individual variability in neurodevelopment and neurodevelopmental disorders.

DOI: https://doi.org/10.64898/2025.12.03.692130
Am J Reprod Immunol. 2025 Dec;94(6): e70198

HIV-Exposed Seronegative Female Sex Workers Show Different Cellular Immune Profiles Across the Menstrual Cycle.

Monika M Kowatsch, Kenneth Omollo, Frideborg Bradley, Anna Månberg, Peter Nilsson, Sofia Bergström, Julius Oyugi, Joshua Kimani, Kristina Broliden, Keith R Fowke, Julie Lajoie.

PROBLEM: Female sex workers (FSWs) are at higher risk of acquiring HIV. Interestingly, some FSWs who are highly exposed remain seronegative for HIV (HESN). This natural resistance to HIV infection has been attributed to an immune quiescence (IQ) phenotype. Our study investigates how the menstrual cycle phases (follicular and luteal) impact the immune responses in Kenyan FSWs.
METHODS: This is a part of the Longitudinal Assessment of Mucosal Immune Quiescence study (LAMIQ), 48 FSWs not living with HIV and not using hormonal contraception were followed for a menstrual cycle and divided into two groups based on duration of sex work: New Negative (NN) with 3 years or less and HESN with at least 7 years of involvement in sex work. We obtained blood and cervicovaginal samples and measured sex hormone, cytokine, and chemokine levels, and blood and endocervical T-cell and NK-cell phenotypes.
RESULTS: We observed differences in how the immune response of NN and HESN responds to sex hormones. Indeed, the level of mucosal Annexin A3 measured was higher during the luteal phase in HESN, which was not observed in NN. HESN exhibited a higher CD39 expression on their Treg during the luteal phase, while maintaining CTLA-4 expression compared to NN. Furthermore, in HESN, NK cell activation varied across the menstrual cycle phases. They had a higher expression of NKG2D and an increase in the cluster of CD95+ HLA-DR+ NK cells during the follicular phase. This suggests stronger innate immune activation in HESN during the follicular phase of the menstrual cycle.
CONCLUSION: Our data indicate that, in HESN, there is a modulation of the immune response based on the menstrual cycle, which potentially limits the availability of HIV target cells at the female genital tract during the luteal phase of the menstrual cycle (window of susceptibility).

DOI: https://doi.org/10.1111/aji.70198
J Therm Biol. 2025 Dec 15. pii: S0306-4565(25)00313-4. [Epub ahead of print]135 104356

Sex and reproductive condition shape thermal acclimation strategy in a plethodontid salamander.

Kevin J Moore, Brittany M Winter, Jeanette B Moss.

  The question of whether males and females differ in their responses to temperature is essential to understanding adaptive capacities in a warming world. However, sex has traditionally been neglected in the field of thermal ecology, and our understanding of the factors that promote sex differences in thermal plasticity is underdeveloped. Here, we investigate the independent and interactive effects of sex and reproductive condition on thermal acclimation capacity in a plethodontid salamander (Plethodon cinereus). We carried out two stop-flow respirometry experiments, with salamanders acclimated to one of two thermal environments designed to simulate a 'Cold' or 'Warm' breeding season. In the first experiment, we compared the thermal acclimation responses of males and gravid females across a gradient of three ecologically relevant test temperatures and observed distinct patterns of sexual dimorphism of metabolic rate (V˙ O2) between thermal treatments that were not attributable to differences in body size. Specifically, warm-acclimated gravid females showed significant reductions V˙ O2 compared to cold-acclimated counterparts, exposing pronounced sexual dimorphism in mass-adjusted metabolic rates at higher test temperatures. In the second experiment, we expanded on our initial findings by directly testing the contribution of reproductive condition to observed sex differences in thermal acclimation capacity. By repeating the experiment of the early breeding season but including a third group of non-gravid females, we: (1) recapitulated our original finding - that gravid females exhibit a stronger response to thermal acclimation relative to males; and (2) showed that female thermal acclimation responses are absent in nongravid females, and therefore responses are contingent on reproductive condition. Taken together, our results provide a first glimpse into how sex and reproductive condition contribute to intraspecific variation in thermal acclimation capacity in an amphibian, and underscore the need for more hypothesis-driven studies to directly test when, where, and how such patterns arise.

Keywords:  Breeding season; Climate change; Metabolic rate; Sex-biased; Temperature sensitivity; Thermal plasticity; Vitellogenesis

DOI:  https://doi.org/10.1016/j.jtherbio.2025.104356
Am J Physiol Heart Circ Physiol. 2025 Dec 19.

Don't sleep on sex differences: circadian influences and considerations in sex-specific research.

Nina L Stute, Casey G Turner.



Keywords:  circadian; inflammation; sex differences

DOI:  https://doi.org/10.1152/ajpheart.00953.2025
Infect Immun. 2025 Dec 16. e0050225

The maternal-infant microbiome axis as an epigenetic and immunometabolic orchestrator: redefining early-life programming and precision interventions for lifelong women's and children's health.

Arpita Mukherjee.

  The maternal-infant microbiome axis represents a dynamic interface that shapes neonatal immune and metabolic development from the earliest stages of life. Microbial communities from the maternal gut, vaginal tract, and breast milk seed the infant microbiome, influencing chromatin remodeling, transcriptional activity, and immunometabolic programming. Rather than functioning solely as a conduit of microbial inheritance, this axis operates as a regulatory network where microbial metabolites such as short-chain fatty acids and indole derivatives modulate histone acetylation, DNA methylation, and noncoding RNA pathways that calibrate immune tolerance and pathogen defense. Perturbations, including cesarean delivery, perinatal antibiotic exposure, or maternal metabolic disorders, disrupt these processes and are associated with altered immune set points, heightened infection susceptibility, and increased risk of inflammatory and metabolic disease. Multi-omics studies now provide mechanistic insights linking microbial signals to epigenetic regulation of neonatal immune responses, while also exposing important controversies, such as the debated presence of a placental microbiome and the variable efficacy of probiotic interventions. Emerging strategies, including maternal dietary modulation of the microbiome, perinatal microbiota restoration, and development of live biotherapeutics, show promise, but their translational potential remains constrained by limited sample sizes, heterogeneous outcomes, and safety concerns. Framing the maternal-infant microbiome axis as an epigenetic and immunometabolic orchestrator highlights both its therapeutic promise and the need for rigorous mechanistic and clinical evaluation to advance preventive strategies for women's and children's health.

Keywords:  early-life intervention; epigenetic programming; immunometabolic regulation; maternal–infant microbiome axis; microbial metabolites; neonatal immunity

DOI:  https://doi.org/10.1128/iai.00502-25
Clin Transl Med. 2025 Dec;15(12): e70541

Single-cell transcriptome analyses reveal disturbed decidual microenvironment in women of advanced maternal age.

Hongliang Xie, Yu Lu, Aolin Zhang, Anqi Zheng, Baofeng Rao, Cuiyu Yang, Anyao Li, Wenbo Guo, Linhua Hu, Xiaoling Huang, Chi Chiu Wang, Songying Zhang, Xiaohui Fan, Lu Li.

   BACKGROUND: Advanced maternal age (AMA) increases pregnancy risk. However, uterine-specific mechanisms independent of oocyte and embryo quality remain poorly defined. This study aimed to characterise the decidual microenvironment in women with AMA to identify key pathological changes and regulatory pathways.
METHODS AND RESULTS: Through integrated histology, organoid modelling, and high-resolution scRNA-seq of first-trimester decidua from women of AMA and controlled reproductive age, we uncovered a pathologically remodelled decidual microenvironment characterised by aberrant cellular states and pathological differentiation pathways, leading to a pro-fibrotic state and accompanied by immune cell dysfunction, and disrupted intercellular communication in the AMA decidua. Central to this pathology was hyperactivated TGF-β signalling, driving fibroblast-to-myofibroblast transition and extracellular matrix overproduction, thereby fuelling fibrosis. Aberrant TGF-β further impaired decidual stromal cell (DSC) differentiation, leading to the failure of the essential mesenchymal-to-epithelial transition. We identified PRR15 as a novel DSC-specific regulator that is markedly suppressed in AMA. PRR15 deficiency unleashed hyperactive TGF-β/SMAD signalling, directly causing decidualisation failure, enhanced fibrosis, and aborted DSC differentiation. Epithelial-mesenchymal transition and immune cell reprogramming towards pro-fibrotic transcriptional signatures further amplify the fibrotic pathology.
CONCLUSION: This study established the aged decidual microenvironment, orchestrated by dysregulated TGF-β signalling and PRR15 loss, as a critical independent determinant of reproductive failure in AMA. Thus, it unveils novel diagnostic and therapeutic targets and strategies.
KEY POINTS: We provide the first single-cell atlas of the human decidua in advanced maternal age (AMA). A novel PRR15-TGF-β axis is identified, where PRR15 loss drives stromal fibrosis and decidualisation failure. This study reveals that AMA-associated uterine fibrosis begins in the first trimester, shifting focus to maternal factors.

Keywords:  advanced maternal age, decidualisation; decidua fibrosis, epithelial–mesenchymal transition, fibroblast–myofibroblast transition, PRR15‐TGF‐β axis, single cell RNA sequencing

DOI:  https://doi.org/10.1002/ctm2.70541
Front Immunol. 2025 ;16 1691163

Estradiol enhances B cell humoral immune responses against genital herpes simplex virus type 2 in mice through an IL-17 dependant pathway.

M Firoz Mian, Ramtin Ghasemi, Puja Bagri, Joshua J C McGrath, Danya Thayaparan, Maysa Niazy, Denis P Snider, Charu Kaushic.

   Introduction: Estradiol has been shown to enhance anti-viral immunity and protect against HSV-2 infection. Previously, we reported that intranasal immunization with attenuated HSV-2 (TK-) in the presence of estradiol (E2) showed enhanced Th17 responses that led to increased anti-viral Th1 immunity in HSV-2 post-challenge. Whether enhanced Th17 cells also lead to improved B cell antibody responses against HSV-2 challenge in immunized mice in the presence of E2 was not examined and is the focus of the current study.
Methods: Ovariectomized (OVX) C57BL/6 or IL-17 knockout (IL-17-/-) mice were implanted with 17β-estradiol (E2) or placebo pellets subcutaneously. Two weeks later, mice were immunized intranasally with a single dose of 104 pfu of TK- HSV-2 and 4- or 6-weeks later, blood sera and vaginal washes were collected to measure IgG total and subtypes by ELISA. Mice were challenged intravaginally with 104 pfu of WT HSV-2 4-6 weeks post-immunization, and vaginal washes were collected daily until euthanized at day 5 post-challenge to determine viral titers and protection. Mononuclear cells isolated from vaginal tract, spleen, nasal associated lymphoid tissue (NALT), cervical lymph nodes (cLN) and iliac lymph nodes (iLN) tissues were analyzed by flow cytometry for plasma and memory B cell phenotypes.
Results: E2-treated WT OVX immunized mice after intravaginal HSV-2 challenge showed significantly increased HSV-2-specific IgG2b and IgG2c antibodies in serum and vaginal secretions compared to placebo mice and enhanced B220-CD138+ IgG2c+ plasma cells within the nasal mucosa and vaginal tract 6-weeks after immunization. Furthermore, E2 treatment enhanced the subsets of CD19+ IgD- memory B cells 4-weeks post immunization within the iLN and spleen. Notably, E2-induced increased B cell antibody responses conferred greater protection from HSV-2 challenge compared to placebo mice as evidenced by 2-3 logs decreased viral titers in the vaginal tract and 20% mice with genital pathology compared to 80% in placebo group, indicating better protection in E2-treated mice. Importantly, E2-mediated enhanced plasma and B cell antibody responses observed in WT mice were abrogated in IL-17-/- mice that led to 2-3 logs higher viral titers that were equivalent in WT placebo- and IL-17-/- mice and no difference in protection.
Conclusion: This study provides novel evidence that part of the E2-induced enhanced anti-viral response is mediated by increased B cell antibody responses that requires IL-17. Thus, E2 could be exploited in developing an effective mucosal vaccine driving B cells through intranasal immunization to elicit stronger HSV-2-specific antibody responses in the female genital tract.

Keywords:  IL-17; TK-HSV-2; estradiol (E2); herpes simplex virus type 2 (HSV-2); intranasal immunization; memory B cells (MBC); plasma cells

DOI:  https://doi.org/10.3389/fimmu.2025.1691163
Eur J Immunol. 2025 Dec;55(12): e70087

Hyperinflammation by Human Macrophages Induced by SARS-CoV-2 Anti-Spike IgG Is Dependent on Glucose and Fatty Acid Metabolism.

Amsterdam UMC COVID‐19 Biobank

  Severe COVID-19 is an immunological disorder characterized by excessive immune activation following infection with SARS-CoV-2, which typically occurs around the time of seroconversion. Anti-spike IgG of critically ill COVID-19 patients induces excessive inflammation by activation of Fc gamma receptors (FcγRs) on human alveolar macrophages, leading to tissue damage, pulmonary edema, and coagulopathy. While metabolic reprogramming of immune cells is critical for the induction of inflammatory responses, still little is known about the metabolic pathways that are involved in COVID-19-specific hyperinflammation. In this study, we identified that anti-spike IgG immune complexes (ICs) induce rapid metabolic reprogramming of alveolar macrophages, which is essential for the induction of inflammation. Through functional inhibition, we identified that glycolysis, fatty acid synthesis, and pentose phosphate pathway (PPP) activation are critical for anti-spike IgG-induced hyperinflammation. Remarkably, while excessive proinflammatory cytokine production by macrophages is critically dependent on simultaneous stimulation with viral stimuli and anti-spike IgG complexes, we show that the required metabolic reprogramming is specifically driven by anti-spike IgG complexes. These findings provide new insights into the metabolic pathways driving hyperinflammation by macrophages in the context of severe COVID-19. Targeting of these pathways may reveal new possibilities to counteract pathological inflammatory responses in severe COVID-19 and related diseases.

Keywords:  COVID‐19; antibodies; immunometabolism; macrophage

DOI:  https://doi.org/10.1002/eji.70087
Cell Rep Med. 2025 Dec 16. pii: S2666-3791(25)00554-3. [Epub ahead of print]6(12): 102481

Association of female reproductive traits with altered aging trajectories: Insights from genetic and observational analyses.

Chen Lou, Guiquan Wang, Zuquan Xiong, Yingxin Celia Jiang, Yan Li, Ming Zhu, Haiyan Yang, Lin Wang, Liying He, Hsun-Ming Chang, Jia Wang, Wencheng Zhu, Xi Dong, Terytty Yang Li, Shuai Yuan, Yue Zhao, Liangshan Mu.

  Women's reproductive health plays a pivotal role in both longevity and the aging process. We conduct Mendelian randomization (MR) and observational analyses to investigate these relationships. Univariate MR analyses reveal that older age at first birth, later menarche, higher estradiol, and sex hormone-binding globulin (SHBG) increase longevity, while pre-eclampsia liability decreases longevity. Older ages at first birth and at first sexual intercourse are associated with lower DNAmGrimAgeAccel, but these associations disappear after mutual adjustment. Mediation analyses identify cardiometabolic diseases, lung diseases, and mental disorders as key mediators. In corroborating the MR results, observational analyses show that early reproductive behaviors, such as age at first sex, are associated with accelerated biological aging. Additionally, we observe significant non-linear associations between hormone levels, age at menopause, and aging outcomes. This study highlights the impact of reproductive health on aging and suggests potential strategies for promoting healthy aging in women.

Keywords:  Mendelian randomization; biological aging; female reproductive traits; longevity; observational analysis

DOI:  https://doi.org/10.1016/j.xcrm.2025.102481
Cell Rep Med. 2025 Dec 16. pii: S2666-3791(25)00578-6. [Epub ahead of print]6(12): 102505

Systemic and mucosal immune signatures of protection against SARS-CoV-2 transmission in humans.

Amaya Rojo-Fernandez, Sadaf Aslam, Fahmida Alam, Alba Escalera, Vicente Villamandos, Beatriz Catón, Gregoria Megías, Angel Gonzalez, Luis Buzón-Martín, Juan Ayllon, Adolfo García-Sastre, Teresa Aydillo.

  Binding and neutralizing antibodies against the spike (S) protein of SARS-CoV-2 have been associated with a reduced risk of symptomatic infection. However, precise immune protection thresholds remain unclear. We aim to define systemic and mucosal antibody correlates of protection against SARS-CoV-2 infection. Our household COVID-19 cohort (the CIDS) consists of 52 families (52 index cases and 139 exposed contacts). Immunoglobulin subtyping against S of SARS-CoV-2 and HCoV-OC43 in the serum and upper respiratory tract is quantified to assess the protection provided by virus-specific pre-existing immunity. Logistic regression analyses indicate that multiple antibody isotypes are associated with reduced infection risk. Specifically, multivariable models show that systemic anti-SARS-CoV-2 S1 IgG and anti-OC43 S2 IgM independently correlate with protection. Besides, local mucosal anti-SARS-CoV-2 S IgG and HCoV-OC43 S IgA antibodies add protective potential. However, an integrated analysis reveals that systemic antibodies against SARS-CoV-2 remain the best predictor against virus infection.

Keywords:  COVID-19; SARS-CoV-2; antibodies; correlates of protection; cross-reactivity; household study; nasal antibodies; seasonal coronaviruses; transmission

DOI:  https://doi.org/10.1016/j.xcrm.2025.102505
Cell Mol Life Sci. 2025 Dec 15.

Oxysterol-mediated modulation of intestinal inflammation: insights into sex differences and GPR183 signaling.

Hafsa Ameraoui, Joan Bestard-Escalas, Martin Roumain, Adam Laghouati, Pauline Bottemanne, Mireille Alhouayek, Giulio G Muccioli.

   BACKGROUND AND AIMS: Oxysterols, oxidized derivatives of cholesterol, play complex roles in inflammatory processes, but their specific functions in inflammatory bowel diseases remain incompletely understood. This study investigates the roles of key oxysterols - 7α,25-dihydroxycholesterol, 25-hydroxycholesterol, 25-hydroxycholesterol-3-sulfate, and 4β-hydroxycholesterol - and potential sex differences in intestinal inflammation.
METHODS: We used complementary approaches including dextran sulfate sodium-induced colitis, and ex vivo studies with colon explants, organoids, and immune cells to examine oxysterol properties. Principal component analysis was employed to analyze variance between disease and sex. In vivo administration of 7α,25-dihydroxycholesterol and NIBR189, an antagonist of its receptor GPR183, was performed to assess effects on inflammatory markers and immune cell trafficking.
RESULTS: We observed sex-specific differences in both basal and colitis-induced oxysterol profiles, with female mice showing greater resistance to dextran sulfate sodium-induced inflammation and distinct patterns of oxysterol metabolism. Principal component analysis highlighted a separation of samples by both treatment and sex, with dextran sulfate sodium treatment accounting for approximately 55% of variance and sex differences explaining 25%. In vitro, 25-hydroxycholesterol-3-sulfate and 7α,25-dihydroxycholesterol decreased inflammatory cytokine expression in colon explants from female mice and reduced cytokine production in THP-1-derived macrophages in a dose-dependent manner. GPR183 antagonists decreased cell activation, suggesting constitutive receptor activity. In vivo 7α,25-dihydroxycholesterol administration showed modest effects on inflammatory markers but significantly decreased immune cell counts in lymph nodes, consistent with altered immune cell trafficking.
CONCLUSION: Our findings reveal sex-specific regulation of inflammatory processes by oxysterols and highlight the therapeutic potential of targeting these pathways in inflammatory bowel diseases.

Keywords:  27-hydroxycholesterol; CYP7B1; Cholesterol-25-hydroxylase; PBMC; IBD; Inflammatory bowel diseases

DOI:  https://doi.org/10.1007/s00018-025-05981-6
Placenta. 2025 Dec 14. pii: S0143-4004(25)00767-2. [Epub ahead of print]174 117-125

NLRP3 inflammasome activation in the placenta during SARS-CoV-2 infection.

Ana María Arboleda-Borrero, Eliécer Jiménez-Charris, Laura Andrea Gómez, Wilmar Saldarriaga, Javier Fonseca, Mildrey Mosquera Escudero.

   BACKGROUND: The NLRP3 inflammasome is a key regulator of innate immunity. Its overactivation contributes to cytokine release and tissue inflammation during SARS-CoV-2 infection. However, its role in placental inflammation and pregnancy outcomes remains unclear.
OBJECTIVE: To evaluate whether SARS-CoV-2 infection during pregnancy induces NLRP3 inflammasome activation in placental tissue and to assess its association with maternal and neonatal outcomes.
METHODS: A prospective cohort study included 25 pregnant women with RT-PCR-confirmed COVID-19 and 25 healthy controls. Placental NLRP3, Caspase-1, IL-1β, and IL-18 expression were analyzed by qRT-PCR and Western blotting. Maternal and cord plasma cytokines were quantified by ELISA and cytometric bead array. Viral RNA, antibody transfer, and nutrient transporter gene expression were also evaluated.
RESULTS: Placentas from infected women showed higher NLRP3 (p = 0.015) and Caspase-1 (p = 0.029) mRNA levels compared with controls. Western blotting detected procaspase-1 (∼50 kDa) and cleaved caspase-1 (∼35 kDa), indicating inflammasome activation. Maternal IL-18 concentrations were elevated (p = 0.013), while IL-1β remained unchanged. SARS-CoV-2 RNA was identified in 8 % of placentas (variants 21H and 20A). IgG antibodies were found in 28 % of maternal and 24 % of cord samples (p = 0.017). Infected pregnancies showed lower gestational age at delivery (p = 0.023), higher cesarean rate (p = 0.004), and lower neonatal Apgar scores (p = 0.006, p = 0.015). Nutrient transporter expression was preserved.
CONCLUSION: SARS-CoV-2 infection during pregnancy induces activation of the NLRP3 inflammasome in placental tissue and systemic elevation of IL-18, indicating both local and systemic inflammation.

Keywords:  COVID-19; Cytokines; Inflammation; NLRP3 inflammasome; Placenta; Pregnancy

DOI:  https://doi.org/10.1016/j.placenta.2025.12.007
Am J Reprod Immunol. 2025 Dec;94(6): e70196

Arginine Metabolism in Decidual Macrophages During Pregnancy.

Yonghong Zhang, Jie Mei, Hui Zhang.

   BACKGROUND: Maternal immune tolerance to the semi-allogeneic fetus is essential for successful pregnancy, while immune defense against pathogens must be preserved. Decidual macrophages (DMs) are critical regulators at the maternal-fetal interface, involved in trophoblast invasion, vascular remodeling, and immune modulation.
METHODS: This review integrates findings from human studies, animal models, and in vitro experiments to explore how arginine metabolism regulates macrophage polarization and pregnancy outcomes.
RESULTS: Arginine metabolism influences DM function via two major pathways: iNOS promotes M1 polarization and pro-inflammatory activity, while Arg-1 supports M2 polarization, tissue remodeling, and immune tolerance. Dysregulation of this balance is associated with pregnancy complications such as pre-eclampsia and fetal growth restriction. Pathogens like Helicobacter pylori and Mycobacterium tuberculosis exploit Arg-1 activity to evade host immunity. Clinical studies also suggest that L-arginine supplementation can improve placental function and fetal growth.
CONCLUSION: Arginine metabolism is a key modulator of macrophage polarization and immune balance in pregnancy. Targeting this pathway may offer novel therapeutic strategies to improve maternal and fetal outcomes.

Keywords:  Arg‐1; arginine; decidual macrophage; iNOS; metabolism; pregnancy

DOI:  https://doi.org/10.1111/aji.70196
Sci Immunol. 2025 Dec 19. 10(114): eadz2294

CD27 agonism enhances long-lived CD4 T cell vaccine responses critical for antitumor immunity.

Bin-Jin Hwang, Erika J Crosby, David T Severson, Timothy N Trotter, Jason McBane, Li-Chung Tsao, Tao Wang, Cong-Xiao Liu, Xiao-Yi Yang, Gangjun Lei, Junping Wei, Xingru Ma, Bushanqing Liu, Amy Hobeika, Michael Morse, Jesuchristopher Joseph, Ethan Agritelley, Elishama Kanu, Karrie Comatas, Tibor Keler, Li-Zhen He, Herbert Kim Lyerly, Zachary C Hartman.

Tumor antigen vaccination represents an appealing approach for cancer but has failed to materialize as oncologic standard of care. To understand long-term vaccine efficacy, we conducted a retrospective analysis of patients with human epidermal growth receptor 2+ (HER2+) breast cancer who received HER2-targeting vaccines and survived for >18 years. PBMC analysis revealed HER2-specific CD27+ memory CD4 and CD8 T cells, suggesting that CD27 signaling supports long-term immune memory. In human CD27 transgenic mice, combining HER2 vaccination with anti-CD27 agonism enhanced HER2-specific responses, particularly long-lived CD4 memory T cells. Murine models demonstrated ~40% tumor regression with combined therapy compared with vaccine alone (~6%). Additional scRNA-seq analysis identified CD4 T cells with a distinct gene expression profile, and depletion/adoptive transfer studies validated that CD4 T cells were essential for this effect. These findings suggest that CD27 agonism enhances vaccine-induced antigen-specific CD4 T cell responses, enabling durable antitumor immunity not entirely dependent on CD8 T cells.

DOI: https://doi.org/10.1126/sciimmunol.adz2294
Am J Physiol Heart Circ Physiol. 2025 Dec 17.

GSNOR deletion differentially alters age-related cardiac function in a sex-dependent manner.

Obialunanma V Ebenebe, Raihan Kabir, Allison Booher, Haley Garbus, Charles D Cohen, Vivek Jani, Brian L Lin, Luigi Adamo, Mark J Kohr.

  S-nitrosoglutathione reductase (GSNOR), a regulator of protein S-nitrosylation (SNO), has been proposed as a longevity protein. GSNOR signaling has been implicated in both the alleviation and exacerbation of aging. In the context of ischemia-reperfusion injury, we previously showed a sex-dependent response to GSNOR inhibition; cardiac damage was alleviated in males and exacerbated in females. Considering sex differences in the incidence of cardiovascular disease with age, we investigated the effect of GSNOR deletion (-/-) on age-related changes in cardiac function. We performed longitudinal 2D-echocardiography measurements in M-Mode on male and female, wildtype (WT) and GSNOR-/- mice at young (3-4 months), middle (13-15 months) and old age (18-20 months). Left ventricular wall thickness and ejection fraction decreased with age in WT mice but was maintained in GSNOR-/-. Western blot and GSNOR activity assays showed GSNOR activity and expression decreased with age in WT females. Isolated cardiomyocyte force-coupling analysis showed increasing age was inversely correlated with sarcomere shortening and Ca2+ release kinetics in WT males, but not GSNOR-/-. WT females showed slower Ca2+ re-uptake after contraction and time to peak sarcomere shortening, but all other parameters were maintained. GSNOR-/- females exhibited slower Ca2+ re-uptake and decreased sarcomere shortening. Proteomic analysis of SNO from females showed increased modification of Pyruvate Dehydrogenase, E1 Beta and Dihydrolipoamide dehydrogenase in young WT females relative to middle-age mice. Together our data suggest that GSNOR deletion is beneficial in males by maintaining cardiac function; while the absence of GSNOR in females removes an age-essential SNO-imbalance, which may exacerbate age-related pathology.

Keywords:  S-nitrosoglutathione reductase; aging; cardiomyocyte function; proteomics; sex differences

DOI:  https://doi.org/10.1152/ajpheart.00681.2025
Physiol Rep. 2025 Dec;13(24): e70670

Sexually dimorphic developmental changes in rat spinal cord pain pathways following neonatal inflammation.

Kateleen E Hedley, Annalisa Cuskelly, Rikki K Quinn, Robert J Callister, Deborah M Hodgson, Melissa A Tadros.

  Early-life inflammation has a long-lasting impact on pain behaviors, with neonatal inflammation resulting in altered pain behaviors throughout life. Possible mechanisms underlying these changes lie within the first and second order neurons in the pain neuroaxis. We investigated neuroinflammatory markers in dorsal root ganglia (DRGs) and spinal cords (SC) of Wistar rats (both sexes) following neonatal injection with either LPS or saline (postnatal days (P) 3 and 5) and isolated tissues in early postnatal development. RT-qPCR revealed acute neuroinflammation in the DRGs, with expression levels of four inflammatory mediators elevated at P7, two at P13, and none at P21 in LPS-treated rats. In contrast, the SC showed no change in inflammatory mediators at P7, elevation of two at P13 and four at P21 in LPS-treated rats. These differences were greater in female SCs, indicating sex-specific modulation even at these early stages of postnatal development. The SCs of P21 LPS-treated rats also showed sex-specific modulation of astrocytes (GFAP), with females showing an increase and males a decrease in GFAP. Together, these data indicate that during early postnatal development DRG neurons are more susceptible to acute inflammation whereas inflammation is delayed in the SC, with sex-specific modulation occurring only in the SC.

Keywords:  Microglia; astrocytes; cytokines; dorsal root ganglai; lipolysaccharide

DOI:  https://doi.org/10.14814/phy2.70670
Proc Natl Acad Sci U S A. 2025 Dec 23. 122(51): e2509977122

Oxytocin varies across the life course in a sex-specific way in a human subsistence population.

Abigail E Colby, Dominik C Jud, Valerie Baettig, Jordan S Martin, Camila Scaff, Michael D Gurven, Benjamin C Trumble, Bret A Beheim, Paul L Hooper, Daniel K Cummings, Hillard Kaplan, Jonathan Stieglitz, Arnulfo Cary Ista, Adrian V Jaeggi.

  Oxytocin, a hormone linked to reproduction and health, may mediate life-history trade-offs across the human life course. Yet, how oxytocin naturally varies with age remains poorly understood. Here, working with the Tsimane, forager-horticulturalists of lowland Bolivia, we collected the largest sample of oxytocin measurements to date (n = 1,242 samples, n = 405 individuals, age = 2 to 84 y, 51% female), and i) examined how oxytocin varies throughout the life course in females and males, and ii) investigated potential drivers of age- and sex-specific variation. Our sample provides rare insight into the relationship between oxytocin and age in a context where energy is limited and trade-offs between reproduction and somatic maintenance are more salient. We found that oxytocin follows a nonlinear sex-specific trajectory throughout the life course. In females, oxytocin levels were high during the reproductive years and declined in the early to midforties, a pattern largely explained by breastfeeding and, to a lesser extent, childcare and good self-rated health. In males, oxytocin was low in early adulthood but high in old age, and although higher oxytocin was linked to good self-rated health, this did not explain the rise in oxytocin in later life. These findings suggest that oxytocin is instrumental for reproduction and caregiving in females and may also be associated with health in both males and females. Together, our work highlights oxytocin's broader biological significance across the human life course, suggesting that it may play a pivotal role in coordinating age- and sex-specific trade-offs involving reproduction and health.

Keywords:  aging; health; hormones; life history; oxytocin

DOI:  https://doi.org/10.1073/pnas.2509977122
Histopathology. 2025 Dec 15.

Apocrine encapsulated papillary carcinoma: a comprehensive clinicopathological analysis of 28 cases.

Ke Zuo, Ruohong Shui, Xiaoli Xu, Baohua Yu, Xiaoyu Tu, Yufan Cheng, Shaoxian Tang, Xiangjie Sun, Rui Bi, Wentao Yang.

   AIMS: Encapsulated papillary carcinoma (EPC) is characterized by neoplastic epithelial cells of low-to-intermediate nuclear grade arranged along fibrovascular cores. Classical EPC typically expresses oestrogen receptor (ER) and usually progesterone receptor (PR), while lacking human epidermal growth factor receptor 2 (HER2) overexpression and gene amplification. In contrast, apocrine encapsulated papillary carcinoma (AEPC), an exceptionally rare tumour with only a few well-characterized cases, exhibits a triple-negative phenotype (ER-, PR-, HER2-). The purpose of this study is to investigate whether the clinicopathological characteristics of AEPC differ from those of classical EPC.
METHODS: Since 2014, 28 cases of AEPC have been identified at the Department of Pathology, Fudan University Shanghai Cancer Centre. We conducted a comprehensive clinicopathological evaluation and prognostic assessment in this case series.
RESULTS: All 28 patients in our study were female, with a median age at diagnosis of 61.5 years (range: 34-90). Fifteen cases were consultation referrals, while 13 cases were diagnosed and treated at our centre. Histologically, all AEPC cases demonstrated cystic architecture with papillary growth patterns. The papillary structures were lined by cells exhibiting uniform apocrine differentiation. The degree of cellular atypia ranged from mild-to-moderate, with no severe atypia identified. Notably, myoepithelial cells were absent in both the papillary structures and lesion peripheries. Among the 28 AEPC cases, 18 were non-invasive, 8 demonstrated microinvasion (<1 mm), and 2 exhibited frank invasion (1-4 mm). The tumour cells exhibited a triple-negative profile and most cases presented with diffuse positivity for androgen receptor (AR) and gross cystic disease fluid protein 15 (GCDFP15). The median Ki-67 proliferation index was 10% (range: 5%-20%). Among the 28 patients, 19 received no adjuvant therapy, while 9 underwent postoperative radiotherapy and/or chemotherapy. With a median follow-up of 44.3 months (range: 7.4-135.5 months) for 27 patients, no recurrences or metastases were observed.
CONCLUSION: Classical EPC typically demonstrates favourable prognosis and is managed as ductal carcinoma in situ. In our study, none of the AEPC patients developed recurrence or metastasis, regardless of adjuvant therapy administration. Although AEPC exhibits a triple-negative immunophenotype, it differs biologically from conventional triple-negative breast cancer (TNBC). The indolent behaviour of AEPC aligns more closely with classical EPC rather than TNBC. Therefore, it may be more appropriate to treat AEPC patients using the same strategies applied to classical EPC.

Keywords:  androgen receptor; apocrine encapsulated papillary carcinoma; triple‐negative breast cancer

DOI:  https://doi.org/10.1111/his.70074
Urologiia. 2025 Nov; 144-150

[Endocrine and metabolic changes in prostate cancer patients after radical prostatectomy].

L Polishchuk D, V Amosova M, A Amosov N, V Fadeev V, V Amosov A, V Vasilieva I, L Demidko Yu.

It has been established that women who undergo hysterectomy, even in cases where the ovaries are preserved, frequently experience premature ovarian insufficiency syndrome, which can lead to various endocrine and metabolic disorders. A comparable inquiry emerges in the context of radical prostatectomy (RP) in males: whether the extraction of the prostate gland itself influences testicular function and the emergence of polymetabolic disorders in the absence of androgen deprivation therapy (ADT). Radical prostatectomy has been recognized as an effective treatment for localized prostate cancer (PCa), providing high survival rates for patients diagnosed with this disease. The primary focus of specialists in this field has historically centered on the surgical consequences of RP, such as erectile dysfunction and stress urinary incontinence. However, mounting evidence suggests that prostate removal itself can also result in a transient decrease in testosterone levels, manifesting as biochemical or manifest hypogonadism, along with moderate metabolic disturbances, though not to the same extent as observed with adjuvant hormone therapy. In some cases, patients already in the preoperative period may have risk factors for metabolic syndrome, osteopenia, and other perioperative complications, which makes it difficult to objectively assess the direct effect of RP. A more profound comprehension of the pathophysiologic mechanisms underlying these changes appears to be a pivotal element in facilitating timely diagnosis, prevention, and treatment of potential endocrine-metabolic complications associated with RP.

Keywords: hypogonadism; metabolic syndrome; prostate cancer; radical prostatectomy; testosterone
Nature. 2025 Dec 17.

Spatiotemporal cellular map of the developing human reproductive tract.

Valentina Lorenzi, Cecilia Icoresi-Mazzeo, Charlotte Cassie, Nadav Yayon, Elias R Ruiz-Morales, Carmen Sancho-Serra, Ryan Colligan, Frederick C K Wong, Magda Marečková, Elizabeth Tuck, Kenny Roberts, Tong Li, Marc-Antoine Jacques, James Ashcroft, Xiaoling He, Berta Crespo, Batuhan Cakir, Simon Murray, Yong Gu, Alexander V Predeus, Martin Prete, Iva Kelava, Roger Barker, Luz Garcia-Alonso, John C Marioni, Roser Vento-Tormo.

The human reproductive tract is essential for species perpetuation and overall health. Its development involves complex processes of sex specification, tissue patterning and morphogenesis, the disruption of which can cause lifelong issues, including infertility1-5. Here we present an extensive single-cell and spatial multi-omic atlas of the human reproductive tract during prenatal development to provide insights beyond those that are possible with smaller-scale, organ-focused studies. We describe potential regulators of sexual dimorphism in reproductive organs and pinpoint previously unknown genes involved in Müllerian duct emergence and regression and urethral canalization of the penis. By combining histological features with gene expression and chromatin accessibility data, we define transcription factors and signalling events potentially involved in the regionalization of the Müllerian and Wolffian ducts. We also refine how the HOX code is established in distinct reproductive organs and reveal that the expression of thoracic HOX genes is increased in the rostral mesenchyme of the fallopian tube and epididymis. Our findings further indicate that epithelial regionalization of the fallopian tube and epididymis, which probably contribute to sperm maturation and capacitation, is established during development. By contrast, later events are necessary for regionalization of the uterocervical canal epithelium. Finally, on the basis of single-cell data and fetal-derived organoids, we show that the fetal uterine epithelium is vulnerable to oestrogen-mimicking endocrine disruptors. By mapping sex-specific reproductive tract regionalization and differentiation at the cellular level, our study provides valuable insights into causes and potential treatments of developmental reproductive disorders.

DOI: https://doi.org/10.1038/s41586-025-09875-2
J Exp Med. 2026 Mar 02. pii: e20241287. [Epub ahead of print]223(3):

Antibiotic use in early life impairs MAIT cell-mediated immunity in adulthood.

Gabrielle R LeBlanc, Adam L Sobel, Jonathan Melamed, Dominic Haas, Eduard Ansaldo, Aiko M Cirone, Elizabeth Murguia, Michael G Constantinides.

Mucosal-associated invariant T (MAIT) cells are predominantly located in barrier tissues where they rapidly respond to pathogens and commensals by recognizing microbial derivatives of riboflavin synthesis. Early-life exposure to these metabolites imprints the abundance of MAIT cells within tissues, so we hypothesized that antibiotic use during this period may abrogate their development. We identified antibiotics that deplete riboflavin-synthesizing commensals and revealed an early period of susceptibility during which antibiotic administration impaired MAIT cell development. The reduction in MAIT cell abundance rendered mice more susceptible to pneumonia, while MAIT cell-deficient mice were unaffected by early-life antibiotics. Concomitant administration of a riboflavin-synthesizing commensal during antibiotic treatment was sufficient to restore MAIT cell development and immunity. Our work demonstrates that transient depletion of riboflavin-synthesizing commensals in early life can adversely affect responses to subsequent infections.

DOI: https://doi.org/10.1084/jem.20241287
Clin Immunol. 2025 Dec 13. pii: S1521-6616(25)00231-1. [Epub ahead of print]283 110656

Long-term immune and epigenetic dysregulation following COVID-19.

Chrysanthi Sidiropoulou, Garyphallia Poulakou, Evdoxia Kyriazopoulou, Elisavet Tasouli, Efthymia Giannitsioti, Anna Strikou, Maria Tsilika, Eirini Christaki, Vassiliki Rapti, Vassiliki Evangelopoulou, Nikoletta Rovina, Nathalie Iannotti, Emanuele Nicastri, Eleonora Taddei, Helena Florou, Andrea Angheben, Matteo Bassetti, Lorenzo Dagna, Antonio Torres, Spyros Foutadakis, George Adamis, Emmanouil Stylianakis, Giannis Vatsellas, Georgia Damoraki, Leda Efstratiou, Christina Damoulari, Konstantinos Leventogiannis, Achilleas Laskaratos, Panagiotis Koufargyris, Nikoletta Charalampaki, Paraskevi Chra, Aglaia Galanopoulou, Dimitris Thanos, Periklis Panagopoulos, Konstantinos Syrigos, Athanasios Ziogas, Rob Ter Horst, Jos W M van der Meer, Konstantina Iliopoulou, Francesco Saverio Serino, Maria Pavlaki, Pierluigi Del Vecchio, Laura Scorzolini, Alessandra Bandera, Agamemnon Bakakos, Styliani Sympardi, Haralampos Milionis, Mihai G Netea, Evangelos J Giamarellos-Bourboulis.

  Post-Acute COVID-19 syndrome (PACS) is heterogeneous in phenotype and functional state. This prospective, observational study studied adults six months after acute COVID-19. We defined clinical phenotypes and profiled plasma mediators grouped into functional pathways (IL-1, IL-17, IFNγ/IFNγ-related cytokines, pro-/anti-inflammatory clusters). A subset underwent RNA-seq and ChIP-seq experiments. Three cohorts were analyzed (Exploratory n = 46; Discovery n = 591; Validation Cohort n = 289). PACS compatible symptoms were identified in 69.6 %; 59.2 % and 54.7 % respectively. Five phenotypes emerged. IL-1 cytokines (OR: 3.17, 95 % CIs: 1.94-5.19, p: 4.5 × 10-6), IL-17 cytokines (OR: 2.45, 95 % CIs: 1.47-4.07 p: 5.88 × 10-4) and the anti-inflammatory biomarkers (OR: 2.15, 95 % CIs: 1.34-3.45, p: 1.5 × 10-3) were upregulated in PACS patients. Respiratory phenotype was correlated with IL-1 upregulation (OR 4.23; 95 % CIs, 1.69-10.8, p = 0.0025). Transcriptomic and epigenomic changes were observed. Distinct phenotypes of PACS are driven by different immunological mechanisms at the DNA, transcriptomic, and protein levels.

Keywords:  Cytokines; IL-1; Immune dysregulation; Lung function tests; Phenotypes; Post-acute COVID-19 syndrome (PACS)

DOI:  https://doi.org/10.1016/j.clim.2025.110656
J Steroid Biochem Mol Biol. 2025 Dec 17. pii: S0960-0760(25)00250-X. [Epub ahead of print]257 106922

Cholecystokinin (CCK) mediates CCKBR to regulate androgen secretion via the steroid pathway in Bactrian camel Sertoli cells.

Qi Wang, Wenjing Wang, Jinghong Nan, Yong Zhang, Xingxu Zhao.

  This study aimed to identify differentially expressed genes (DEGs) in the testes of Bactrian camels during estrus and anestrus and investigate the regulatory role of cholecystokinin (CCK) and its receptor (CCKBR) in androgen synthesis. RNA sequencing was performed on six testicular samples (estrus, n = 3; anestrus, n = 3). A total of 291 DEGs were identified, including 27 upregulated and 264 downregulated in estrus. Gene Ontology (GO) enrichment analysis revealed that CCKBR was significantly enriched in reproduction-related pathways, and STRING analysis showed a close association between CCK and CCKBR. Further qRT-PCR, Western blot, and immunofluorescence (IF) analyses demonstrated significantly higher mRNA and protein levels of CCK/CCKBR in estrus testes (P < 0.01), with both localized in Sertoli cells, Leydig cells, primary spermatocytes, and spermatogonia. Primary Sertoli cells, confirmed by WT1 co-localization, were transfected with p-IRES2-EGFP-CCK and siRNA-CCK. Results showed that CCK overexpression significantly reduced testosterone (T) and dihydrotestosterone (DHT) levels (P < 0.05), while upregulating androgen receptor (AR) and key androgen synthesis enzymes (StAR, P450scc, 3β-HSD) (P < 0.05 or P < 0.01). In contrast, siRNA-CCK exerted the opposite effects. In conclusion, our study highlights the CCK/CCKBR axis as a crucial regulator of seasonal testicular function in Bactrian camels, with CCK negatively regulating testicular androgen synthesis by modulating AR and androgen synthesis enzymes. These findings provide valuable insights into the reproductive biology of Bactrian camels and offer a novel pathway for understanding seasonal fertility regulation in male mammals. This has important implications for enhancing camel breeding efficiency and supporting conservation efforts.

Keywords:  Androgen; Bactrian camel; CCK/CCKBR; Sertoli cells; Steroid pathway

DOI:  https://doi.org/10.1016/j.jsbmb.2025.106922