bims-simsho 2025-06-22 papers

bims-simsho

Biomed News

on Systems immunology and sex hormones

Issue of 2025–06–22
fifteen papers selected by
Chun-Chi Chang, Lunds universitet

The Placental Steroid Hypothesis of Human Brain Evolution.
Association between serum testosterone and measures of cardiovascular health among transgender individuals using gender-affirming testosterone therapy: a cross-sectional study.
Trajectories and dimensional phenotypes of depressive symptoms throughout pregnancy and postpartum in relation to prior premenstrual symptoms.
Impact of a moderate-intensity aerobic exercise intervention on systemic and uterine natural killer cells in women with unexplained recurrent pregnancy loss.
Bacterial vaginosis.
Comprehensive transcriptome assessment in PBMCs of post-COVID patients at a median follow-up of 28 months after a mild COVID infection reveals upregulation of JAK/STAT signaling and a prolonged immune response.
Research Progress on Inflammation and Immune Dysregulation in PTSD.
Clinical pearls addressing hair growth and loss in transgender patients on hormone replacement therapy.
Efficacy of intravenous immunoglobulin in recurrent pregnancy loss: a retrospective analysis of patients with abnormal cellular immunity.
Interferon-β and interleukin-6 exert opposing effects on Foxp3 acetylation to control regulatory T cell induction.
Landscape of targets within nucleoside metabolism for the modification of immune responses.
Advances in vaccine adjuvant development and future perspectives.
Sex Hormone-Binding Globulin Controls Sex-Specific Lipolytic Activity in Human Abdominal Subcutaneous Adipocytes.
Effect of Bacillus Subtilis BN Strain on M1 Macrophage Antiviral Response.
Serotonin, immune function, and psychedelics as potent anti-inflammatories.

Evol Anthropol. 2025 Jun;34(2): e70003

The Placental Steroid Hypothesis of Human Brain Evolution.

Alex Tsompanidis, Graham J Burton, Simon Baron-Cohen, Robin I M Dunbar.

The evolution of the human brain has long been framed in terms of sexual selection, with an emphasis on consistent but small on-average volumetric differences between males and females. In this review, we present new molecular, genetic and clinical findings regarding neurodevelopment, cortical expansion and the production of sex steroid hormones, such as testosterone and oestradiol, by the placenta during pregnancy. We discuss converging evidence that on-average sex differences are relevant for human evolution but are characterised by significant overlap between the sexes and more adaptations in female, rather than male, physiology. We also consider recent accounts and modelling of evolutionary pressures in large social groups, regarding competition and fertility. Finally, we bring these findings together and present a novel hypothesis for understanding human brain development and evolution, which emphasises the role of sex steroid hormones, their prenatal production by the placenta and their roles in regulating physiology, fertility and cognition.

DOI: https://doi.org/10.1002/evan.70003
Biol Sex Differ. 2025 Jun 17. 16(1): 44

Association between serum testosterone and measures of cardiovascular health among transgender individuals using gender-affirming testosterone therapy: a cross-sectional study.

Badal S B Pattar, Tyrone G Harrison, Nathalie Saad, Sandra M Dumanski, A J Lowik, Paul E Ronksley, Dina N Greene, Cameron T Whitley, Chantal L Rytz, Keila Turino Miranda, Lindsay Peace, Amelia M Newbert, Darlene Y Sola, Sofia B Ahmed.

   BACKGROUND: Gender-affirming testosterone therapy (GATT) use may be associated with increased systolic blood pressure (SBP). The association between serum testosterone and cardiovascular health in individuals using GATT is unknown. The objective of this study was to estimate the association between serum testosterone and validated measures of cardiovascular health, including SBP and arterial stiffness, in persons assigned female sex at birth using GATT.
METHODS: Healthy participants assigned female sex at birth on a stable GATT regimen for ≥ 4 months were recruited to this community-partnered exploratory cross-sectional study. Exposures of interest were total and free serum testosterone concentration. As our primary outcome, SBP was measured by an automated sphygmomanometer, and carotid-radial pulse wave velocity (PWVcr) and aortic augmentation index (AIx) were used to measure arterial stiffness via applanation tonometry.
RESULTS: Participants (n = 18, median age 28 years, range: 18, 50) who predominantly self-identified as white (94%) and had been using GATT for a median of 48 months (range: 5, 84) were studied. Resting SBP, PWVcr, and AIx were 113 mmHg (range: 102, 129), 7 m/s (range: 4, 9), and 9% (range: - 10, 23), respectively. Total and free serum testosterone were not significantly associated with SBP or PWVcr. Free, but not total, serum testosterone was positively associated with AIx (p = 0.03). Sensitivity analyses did not modify any results.
CONCLUSIONS: In healthy transgender individuals, serum testosterone concentrations may not be associated with measures of cardiovascular health. However, these results need to be interpreted with caution given the limited sample size.

Keywords:  Arterial stiffness; Blood pressure; Cardiovascular health; Gender-affirming hormone therapy; Serum testosterone; Testosterone; Transgender

DOI:  https://doi.org/10.1186/s13293-025-00726-3
Br J Psychiatry. 2025 Jun 20. 1-9

Trajectories and dimensional phenotypes of depressive symptoms throughout pregnancy and postpartum in relation to prior premenstrual symptoms.

Ella Schleimann-Jensen, Inger Sundström-Poromaa, Samantha Meltzer-Brody, Tory A Eisenlohr-Moul, Fotis C Papadopoulos, Alkistis Skalkidou, Erika Comasco.

   BACKGROUND: Sensitivity to ovarian hormone fluctuations can lead to mental distress during the luteal phase of the menstrual cycle, such as in premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD), and also during pregnancy and postpartum, as in perinatal depression (PND).
AIMS: In two cohorts, we investigated the relationship between history of PMS/PMDD and PND symptoms. We also examined how premenstrual symptoms are associated with perinatal symptom trajectories and dimensional phenotypes of PND symptoms, which remains unidentified.
METHOD: From early pregnancy until 6 months postpartum, participants of two large longitudinal cohorts were followed using the Edinburgh Postnatal Depression Scale (EPDS). Premenstrual symptoms were self-reported retrospectively.
RESULTS: Both pre-pregnancy PMS and PMDD were associated with higher EPDS scores across pregnancy and postpartum, even after adjustment for confounders. The odds of developing PND were higher among those reporting PMS and PMDD, ranging up to 1.68 (95% CI 1.25-2.29) (6-13 weeks postpartum) and 3.05 (95% CI 2.26-4.10) (late pregnancy) respectively for PMS and PMDD, throughout the perinatal period. Premenstrual symptomatology was associated more with certain PND trajectories based on the time of occurrence and persistence of symptoms. However, PND symptom severity did not differ depending on premenstrual symptomatology in any trajectory. Prior PMS/PMDD was associated with underlying dimensions of symptom constructs of PND, including severe and moderate symptoms of depressed mood, anxiety and anhedonia.
CONCLUSIONS: Women with a history of PMS/PMDD require coordinated care by psychiatrists, other mental health clinicians, midwives and gynaecologists during pregnancy as well as postpartum.

Keywords:  Reproductive psychiatry; ovarian hormones; perinatal depression; premenstrual disorder; women

DOI:  https://doi.org/10.1192/bjp.2025.38
Front Immunol. 2025 ;16 1602939

Impact of a moderate-intensity aerobic exercise intervention on systemic and uterine natural killer cells in women with unexplained recurrent pregnancy loss.

Aysel Gurbanova, Amber E M Lombardi, Denise H J Habets, Salwan Al-Nasiry, Marc E A Spaanderman, Marien I de Jonge, Tess Meuleman, Lotte Wieten, Renate G van der Molen.

   Introduction: Recurrent pregnancy loss (RPL) is associated with altered immune phenotypes and functions. It has been proposed that physical exercise might impact the immune system. Therefore, we evaluated the effect of a personalized 3-month moderate-intensity aerobic exercise intervention on the immune system of women with unexplained RPL (uRPL). Given the suggested supportive role of Natural Killer (NK) cells during early pregnancy, we focused on numerical, phenotypic, and functional changes in peripheral NK (pNK) and uterine NK (uNK) cells.
Methods: Mononuclear cells were isolated from peripheral blood (PB) (n=23) and menstrual blood (MB) (n=22) of women with uRPL. NK cell phenotypes were assessed with comprehensive flow cytometry panels. NK cell function was assessed with degranulation assays and intracellular staining of interferon-γ (IFN-γ), perforin and granzyme-B in a subgroup of women due to lower availability of samples (n=12).
Results: Attendance to the exercise intervention was overall 95%, which resulted in effects on the phenotype and function of pNK cells. We found a significant reduction in the median fluorescent intensity of CD161 (464 vs 410, p=0.011), NKp30 (432 vs 376, p=0.018), and NKG2A (886 vs 732, p=0.039) in pNK cells after exercise, while no differences were observed in uNK cells. We also observed decreased percentages of IFN-γ+ pNK cells (49% vs 25.2%, p=0.027) after exercise.
Discussion: Our study shows promising results, suggesting that exercise can impact pNK cell phenotype and function in women with uRPL. Following the changes in pNK phenotype and function suggest a lower pro-inflammatory state post-exercise. Whether these exercise-induced phenotypic and functional changes of pNK cells impact subsequent pregnancies remains to be studied. The study details are available through HYPERLINK "https://clinicaltrials.gov/"Home | ClinicalTrials.gov, trial ID: HMOVE.

Keywords:  NK cells; exercise intervention; immunophenotyping; menstrual blood; recurrent pregnancy loss (RPL)

DOI:  https://doi.org/10.3389/fimmu.2025.1602939
Nat Rev Dis Primers. 2025 Jun 19. 11(1): 43

Bacterial vaginosis.

Catriona S Bradshaw, Erica L Plummer, Christina A Muzny, Caroline M Mitchell, David N Fredricks, Melissa M Herbst-Kralovetz, Lenka A Vodstrcil.

Bacterial vaginosis (BV) is a vaginal microbiome disorder that is associated with preterm birth and spontaneous abortion, increased risk of HIV infection and sexually transmitted infections, and has negative effects on quality of life. BV affects one in four women globally, with the highest burden in resource-limited settings. Marked alterations in vaginal microbiome composition, in pro-inflammatory cytokines and chemokines, and in the proteome and metabolome characterize BV and contribute to adverse sequelae. Despite its prevalence, the exact aetiologic agent of BV is unknown and its pathophysiology is poorly understood. These knowledge gaps impede diagnostic and management approaches, with recommended treatment strategies resulting in recurrence that exceeds 50% over 3-6 months. New data on the sexual transmission of BV, including evidence that male-partner treatment improves cure, have improved our understanding of its aetiology and pathogenesis, and provide opportunities for developing optimal diagnostic, treatment and prevention strategies. Other factors probably also contribute to the low efficacy of current treatments, including biofilm and/or antimicrobial resistance, and failure to recolonize a favourable vaginal microbiome after treatment. The complex pathophysiology of BV highlights that individualized and multifaceted management approaches will be required to manage the refractory and adverse sequelae of BV.

DOI: https://doi.org/10.1038/s41572-025-00626-1
Front Immunol. 2025 ;16 1589589

Comprehensive transcriptome assessment in PBMCs of post-COVID patients at a median follow-up of 28 months after a mild COVID infection reveals upregulation of JAK/STAT signaling and a prolonged immune response.

Serena Fineschi, Joakim Klar, Juan Ramon Lopez Egido, Jens Schuster, Jonas Bergquist, René Kaden, Niklas Dahl.

   Background: Post-acute sequelae of SARS-CoV-2 infection (PASC), also known as post-COVID-19 condition (here abbreviated as post-COVID) is an escalating global health issue. The aim of our study was to investigate the mechanisms and clinical manifestations of post-COVID following a mild SARS-CoV-2 infection.
Methods: We analyzed the gene expression profile in PBMCs from 60 middle-aged post-COVID patients and 50 age-matched controls at a median time of 28 months following a mild SARS-CoV-2 infection. The clinical assessments included intensity of post-COVID symptoms, physical and mental fatigue, depression and anxiety. Sixty-seven participants performed a mild exertion ergometer test with assessment of lactate concentrations. Transcriptome analysis was performed on mRNA selected by poly-A enrichment and SARS-CoV-2 RNA fragments were analyzed using the ARTIC protocol.
Results: We identified 463 differentially expressed transcripts in PBMCs, of which 324 were upregulated and 129 downregulated in post-COVID patients. Upregulated genes in post-COVID individuals were enriched for processes involving JAK-STAT signaling, negative regulation of ubiquitination, IL9 signaling, and negative regulation of viral process, suggesting chronic inflammation. Downregulated genes were enriched for processes involving mitochondrial ATP synthesis, and oxidative phosphorylation, suggesting mitochondrial dysfunction. No SARS-CoV-2 gene fragments were detected in PBMCs of patients with post-COVID and no IFN genes were found differentially expressed in post-COVID patients. Post-COVID was associated with elevated lactate levels in blood, both at rest and after a short recovery phase following exertion, suggesting increased anaerobic activity in skeletal muscles. We did not find differences in the transcriptional profiles or clinical manifestations when comparing patients who contracted the infection from early SARS-CoV-2 variants with those who contracted the infection during the period when the Omicron variant was prevalent.
Conclusions: Our findings highlight molecular changes compatible with a persistent immune response in PBMCs of post-COVID subjects at a median follow-up of 28 months after a mild infection, supporting the hypothesis that post-COVID is a chronic inflammatory condition. The upregulation of JAK/STAT signaling suggests a potential therapeutic target in post-COVID.

Keywords:  JAK/STAT signaling; RNA sequencing; SARS-CoV-2; interferon signature; interleukin 9; mitochondrial dysfunction; post-COVID; ubiquitination

DOI:  https://doi.org/10.3389/fimmu.2025.1589589
Brain Behav. 2025 Jun;15(6): e70633

Research Progress on Inflammation and Immune Dysregulation in PTSD.

Luodong Yang, Jiaying Lu, Zhiqiang Zhao, Ziwei Zhang, Weiliang Yang, Guiqing Zhang.

   INTRODUCTION: Post-traumatic stress disorder (PTSD) is a severe psychological condition triggered by traumatic events, commonly characterized by symptoms such as re-experiencing traumatic memories, avoidance, hyperarousal, and disturbances in cognition and emotions. While PTSD is often viewed through a psychological lens, increasing evidence highlights its strong association with immune system dysfunction and inflammation. This narrative review summarizes recent research progress on the role of inflammation and immune dysregulation in PTSD, highlighting key findings and their implications for understanding the pathophysiology of the disorder.
METHODS: We conducted a search in the PubMed and Web of Science databases using the keywords "PTSD" and "related inflammatory markers" and discussed the existing literature on the relationship between PTSD and inflammatory responses.
RESULTS: The research indicates that PTSD is marked by significant imbalances in pro-inflammatory and anti-inflammatory cytokines across various biological fluids, including blood, saliva, and cerebrospinal fluid. Abnormal immune cell activation and elevated levels of soluble adhesion molecules, chemokines, and markers of inflammation were frequently observed in PTSD patients. These inflammatory responses are accompanied by aberrant activity in central immune cells, suggesting that inflammation may play a key role in the pathogenesis of PTSD. In addition, neuroinflammatory processes were linked to cognitive and emotional disturbances commonly seen in individuals with PTSD.
CONCLUSION: Our findings suggest that immune system dysfunction and inflammation are integral components of PTSD pathology. Understanding the mechanisms of neuroinflammation and immune dysregulation could facilitate the early identification of individuals at high risk for PTSD and pave the way for inflammation-targeted therapies. Future research should focus on developing novel anti-inflammatory interventions to complement existing therapeutic approaches, potentially offering new avenues for precision treatment strategies for PTSD.

Keywords:  immune cells; immune genes; inflammatory cytokines; pathological mechanisms; post‐traumatic stress disorder

DOI:  https://doi.org/10.1002/brb3.70633
Dermatol Online J. 2025 Feb 15. 31(1):

Clinical pearls addressing hair growth and loss in transgender patients on hormone replacement therapy.

Chinenye Onejeme, Mary Fitzgibbon, Antonio Jimenez, Lindy Ross.

Hair is a defining feature of human appearance and plays an essential role in personality and identity development. Currently, about 1.6% of US adults identify as transgender. Within the transgender community, hair serves not only as a means of self-expression but also as a crucial element in affirming gender identity, helping individuals to align their outward appearance with their inner sense of self. However, there are significant disparities in the care provided to transgender patients, particularly those seeking a more masculine or feminine appearance through hormone replacement therapy. Studies on transgender patient satisfaction with current therapies are limited but indicate overall dissatisfaction with the standard of care. Dermatologists play a pivotal role in advocating and caring for transgender patients regarding their hair and skin needs. A deeper understanding of hormone replacement therapy and hair growth/loss therapy is crucial to prescribing medications aligned with patients' treatment goals. This commentary aims to provide clinical guidance to dermatologists, aiding them in educating transgender patients undergoing hormone replacement therapy about accessible options for hair growth and loss. Treatment algorithms have been proposed based on efficacy, pharmacodynamic interactions with hormone replacement therapy, cost-effectiveness, adverse reactions, and care accessibility tailored specifically for transfeminine and transmasculine patients.

DOI: https://doi.org/10.5070/D331164961
Front Endocrinol (Lausanne). 2025 ;16 1546602

Efficacy of intravenous immunoglobulin in recurrent pregnancy loss: a retrospective analysis of patients with abnormal cellular immunity.

Jae Won Han, Jin Sol Park, Jong-Seok Kim, Sung Ki Lee.

   Introduction: Various causes of recurrent pregnancy loss (RPL) have been identified, but even with a detailed evaluation, almost half of the cases have unidentified etiologies. Immune imbalance is one of the proposed potential etiologies of these idiopathic RPL. To regulate abnormal cellular immunity, intravenous immunoglobulin (IVIG), a type of immunotherapy, is proposed to improve pregnancy outcomes. However, the efficacy of IVIG in RPL is still controversial.
Methods: RPL was defined as women with two or more spontaneous abortions and in total, 987 RPL women visited Department of Obstetrics and Gynecology, Konyang University Hospital from January 2007 to December 2020. Only those with a full evaluation and known treatment outcome were included. Idiopathic RPL(n=215) and women with known etiology (n=251) were enrolled. Both the idiopathic and known etiology groups were subsequently stratified into subgroups based on the presence of at least one abnormal cellular immunity (n=100 and n=97, respectively). We investigated the pregnancy outcome by sorting the patients into seven subgroups depending on abnormal cellular immunity including natural killer (NK) cell level, NK cell cytotoxicity and Th1/Th2 ratio.
Results: Patients with older age and higher body mass index had negative effect on pregnancy outcomes whereas the number of previous miscarriages did not show significant difference in pregnancy outcomes. Among all RPL women with at least one abnormal cellular immunity were treated with IVIG and the overall live birth rate (LBR) was 82.7%. The group which did not have IVIG treatment showed an overall LBR of 80.7%. Among the seven groups of idiopathic RPL women with abnormal cellular immunity, the group with both high NK cell level and NK cell cytotoxicity showed the highest LBR, 90.5%, and the group with both high NK cell level and Th1/Th2 ratio showed the lowest LBR, 75%.
Discussion: IVIG treatment appears to improve LBRs in women with RPL and abnormal cellular immunity. These findings support the potential benefit of IVIG in selected RPL patients with immune imbalances. Further studies are needed to refine patient selection criteria and optimize treatment protocols for improving pregnancy outcomes in this population.

Keywords:  TH1/TH2 ratio; immunity; intravenous immunoglobulin; natural killer cell cytotoxicity; natural killer cells; recurrent pregnancy loss

DOI:  https://doi.org/10.3389/fendo.2025.1546602
Front Immunol. 2025 ;16 1593931

Interferon-β and interleukin-6 exert opposing effects on Foxp3 acetylation to control regulatory T cell induction.

Mehek Ningoo, Francisco Fueyo-González, Cayetana Gisbert-Vilanova, Laura Espinar-Barranco, Nada Marjanovic, Miguel Fribourg.

  Cytokines are key soluble signaling molecules that regulate immune responses. With the advent of therapies that selectively target cytokines and cytokine receptors, understanding the molecular mechanisms underpinning how immune cells integrate multiple cytokine signals has become a critical challenge in immunology. However, the pleiotropic nature of cytokines makes it difficult to decipher their precise contributions in various contexts. Here, we used an integrated experimental and computational approach to investigate the combined effect and interplay between the pro-inflammatory cytokine interleukin-6 (IL-6) and interferon-beta (IFNβ), also a pro-inflammatory cytokine with potent antiviral properties, in modulating regulatory T cell (Treg) induction. Our studies reveal that, in contrast with its pro-inflammatory role in innate immune responses, IFNβ can counteract the well-described inhibitory effect of IL-6 on Treg induction. Mechanistically, we demonstrate that IFNβ and IL-6 signal independently to promote opposing effects on the acetylation of Foxp3, an essential transcription factor governing Treg differentiation, stability, and function. We further show that this mechanism is conserved in both murine and human T cells, highlighting the broad relevance of this finding in immune regulation. These results have important implications for the numerous contexts in which IFNβ and IL-6 co-exist, including viral infection, transplantation, and autoimmune disease.

Keywords:  acetylation; interferon-beta; interleukin-6; regulatory T cells; tocilizumab

DOI:  https://doi.org/10.3389/fimmu.2025.1593931
Front Oncol. 2025 ;15 1483769

Landscape of targets within nucleoside metabolism for the modification of immune responses.

Ella M Dunderdale, Evan R Abt.

  Nucleoside metabolism regulates immune cell development and function, but the therapeutic implications of this link have yet to be fully realized. Evidence for the importance of nucleoside metabolism in immune system control was provided by observations of immunodeficiency and autoimmunity across patients with genetic errors that alter nucleoside synthesis or breakdown. Research over the past several decades has uncovered a multifaceted role for nucleosides in mediating immune responses that involves their function as metabolic precursors and as ligands for immune receptors. These findings prompted the development of treatments that block the production of the immunosuppressive nucleoside adenosine for cancer immunotherapy. Guanosine and pyrimidine nucleosides also mediate immune outcomes, and the key regulators of their metabolism are promising new targets to unleash anti-cancer immune responses or dampen autoimmune reactions. This review provides an overview of (i) recent research concerning the mechanisms underlying nucleoside-mediated immune regulation, (ii) the current landscape of therapeutic targets for immune modulation within nucleoside metabolism, and (iii) opportunities for developing improved preclinical models that recapitulate human nucleoside metabolism, which are needed to advance new metabolism-targeting therapies toward the clinic.

Keywords:  autoimmune disease; cancer immunotherapy; immune activation; immuno-metabolism; metabolism; nucleotide metabolism

DOI:  https://doi.org/10.3389/fonc.2025.1483769
Drug Deliv. 2025 Dec;32(1): 2517137

Advances in vaccine adjuvant development and future perspectives.

Genada Sinani, Sevda Şenel.

  Use of highly purified antigens to improve vaccine safety has led to reduced immunogenicity and efficacy, resulting in the need for adjuvants to increase and/or modulate the immunogenicity of the vaccine. Despite the need for potent and safe vaccine adjuvants, currently, there are still very few adjuvants in licensed human vaccines. Advances in immunology and molecular biology, especially in the last decade, have allowed researchers to understand better how the adjuvants work and enhance immune responses. While aluminum salts are still the most widely used adjuvants, research has shifted toward the rational design of adjuvant systems containing immunostimulatory molecules. Application of systems biology, which is based on high-throughput technologies using mathematical and computational modeling, has provided a deeper understanding of the biological events elicited by vaccination as well as the influence of other factors such as sex, age, microbiota, genetics and metabolism on the immune response. By this means, it became possible to tailor potential vaccine adjuvants more precisely for a successful vaccine with enhanced efficacy, safety and protection. In this review, after describing the mechanism of action of the adjuvants, current adjuvants in licensed vaccines, as well as those under clinical development will be mentioned in detail. Finally, new approaches in vaccine adjuvant development using systems biology and artificial intelligence will be reviewed, and future directions in vaccine research in regard to efficacy, safety and quality aspects will be discussed.

Keywords:  Clinical trials; licensed vaccine adjuvants; mechanism of action; metabolic and epigenetic adjuvants; microbiota; systems biology; tissue-resident memory responses

DOI:  https://doi.org/10.1080/10717544.2025.2517137
Mol Metab. 2025 Jun 16. pii: S2212-8778(25)00096-1. [Epub ahead of print] 102189

Sex Hormone-Binding Globulin Controls Sex-Specific Lipolytic Activity in Human Abdominal Subcutaneous Adipocytes.

Julie Abildgaard, Aiste Aleliunaite, Carla Horvath, Nagendra Palani, Tora Ida Henriksen, Jiawei Zhong, Katja Munch Lorentsen, Victor Svenstrup, Hanne Frederiksen, Anders Juul, Camilla Charlotte Scheele, Søren Nielsen.

Regulation of lipid metabolism is fundamental for metabolic health, and adipose tissue is a central component in this process. Adipose tissue differs considerably between women and men in terms of a higher subcutaneous capacity for storage, which is linked to metabolic health, in women. Sex hormone-binding globulin (SHBG) contributes to the regulation of circulating sex hormone bioavailability and has been shown to predict risk of metabolic dysfunction. Here, we investigate the sex-specific relationship of SHBG with metabolic status and adipocyte-dependent lipolysis. We measured serum concentrations of sex hormones, SHBG, fasting glucose, and insulin in a cohort of 63 women and 27 men from which adipose biopsies were collected and mature adipocytes isolated. In women, high serum SHBG concentrations were strongly associated with low in vivo Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), and lower unstimulated ex vivo lipolysis but higher isoprenaline stimulated ex vivo lipolysis. In contrast, no effect of SHBG on the above-mentioned parameters were observed in men. In vitro cultured human adipocytes also increased lipolytic activity in response to SHBG, but only in the absence of testosterone, suggesting that testosterone inhibits the catecholamine-induced lipolysis of SHBG in adipose tissue. In conclusion, we identify SHBG as a novel sex-specific regulator of adipocyte lipolysis and lipid metabolism. At the same time, our data emphasize sex-dependent effects of SHBG on adipocyte lipid metabolism, and we propose testosterone binding to SHBG as a driving factor mediating these sex differences.

DOI: https://doi.org/10.1016/j.molmet.2025.102189
Cell Biochem Funct. 2025 Jun;43(6): e70091

Effect of Bacillus Subtilis BN Strain on M1 Macrophage Antiviral Response.

Keisuke Tobita, Manami Sawahata, Keiichiro Imaizumi, Keiko Kotsuna, Takanori Miyoshi.

  M1 macrophages play an important role in pathogenic microorganism infection. Natto, a traditional fermented food from Japan, has long been thought to prevent infection by pathogenic microorganisms. Bacillus subtilis BN strain, which has been isolated from natto, is used in animal feed, health food products, and pharmaceuticals as a probiotic capable of regulating intestinal flora and immunomodulates. The purpose of this study is to investigate the effects of B. subtilis BN strain on the antiviral immune function of human M1 macrophages. The M1 macrophages studied here were derived from a human monocytic cell line (THP-1). Overall, we found that B. subtilis BN strain enhanced gene expressions of antiviral and anti-inflammatory cytokines in M1 macrophages and M1 macrophages stimulated with resiquimod in a cell culture model that mimics single-stranded RNA virus infection. In M1 macrophages, B. subtilis BN strain was also found to promote the gene expression and phosphorylation of key molecules in the toll-like receptor signaling pathways. Furthermore, the BN strain induced the expression of some cytokine mRNA was reduced by the knockdown of NFκB in M1 macrophages. Taken together, these results suggest that toll-like receptor signal pathways are involved in the regulation of antiviral and anti-inflammatory cytokine gene expressions induced by the BN strain in M1 macrophages.

Keywords:  Bacillus subtilis; THP‐1; antivirus; macrophage; natto

DOI:  https://doi.org/10.1002/cbf.70091
Int Rev Neurobiol. 2025 ;pii: S0074-7742(25)00026-1. [Epub ahead of print]181 45-76

Serotonin, immune function, and psychedelics as potent anti-inflammatories.

Charles D Nichols, Timothy P Foster.

  Psychedelics are primarily recognized for their profound behavioral effects, leading most research on psychedelics and their primary target, the 5-HT2A receptor, to focus on brain activity. However, these receptors are not only found within the brain and are present in nearly every tissue and cell type throughout the body, playing a significant role alongside serotonin in modulating various processes, including immune function. Serotonin acting at 5-HT2A receptors generally promotes inflammation. Levels are elevated at sites of inflammation and through 5-HT2A receptor activation lead to events including increased cytokine production, eosinophil recruitment, T-cell activation, and mast cell degranulation. Some psychedelics, but not all, have been found to have powerful anti-inflammatory and immunomodulatory effects through activation of 5-HT2A receptors in preclinical experimental systems and models of human inflammatory diseases. Human studies examining anti-inflammatory effects of psychedelics are limited but suggestive that psychedelics may represent a new strategy to treat inflammatory diseases. In this review we will present an overview of serotonergic modulation of immune function, the role of 5-HT2A receptors in these processes, and a summary of key findings with psychedelics with regards to anti-inflammatory efficacy.

Keywords:  5-HT2A; Anti-inflammatory; Immune system; Psychedelics; Serotonin

DOI:  https://doi.org/10.1016/bs.irn.2025.04.011