bims-simsho Biomed News
on Systems immunology and sex hormones
Issue of 2025–06–08
fourteen papers selected by
Chun-Chi Chang, Lunds universitet
  1. Social, microbial, and immune factors linking bacterial vaginosis and infectious diseases.
  2. Impact of Gut and Reproductive Tract Microbiota on Estrogen Metabolism in Endometriosis.
  3. Drug repurposing reveals posaconazole as a CYP11A1 inhibitor enhancing anti-tumor immunity.
  4. Sex and age differences in cortisol levels during glucagon stimulation test in children.
  5. Understanding the Link Between Hormonal Changes and Gingival Health in Women: A Review.
  6. The reciprocal regulation between autophagy and IL-22: implications for immunity and therapy.
  7. Vaginal Microbiome Dominated by Lactobacillus Positively Impacts Clinical Pregnancy in Patients With Frozen Embryo Transfers.
  8. Multicenter cohort study of the effect of Crinone® progesterone vaginal gel alone to prepare the endometrium for frozen-thawed blastocyst transfer in a hormone replacement cycle.
  9. Microbiome in prostate cancer: pathogenic mechanisms, multi-omics diagnostics, and synergistic therapies.
  10. Divergence in the Sow Vaginal Microbiota is Associated with Fertility.
  11. Reprogrammed immuno-metabolic environment of cancer: the driving force of ferroptosis resistance.
  12. Crosstalk of immunity and metabolism: interaction of toll-like receptors (TLRs) and gut microbiota.
  13. Molecular basis of autoimmune disease protection by MDA5 variants.
  14. Integrated lipidomics and metabolomics approach to assess sex-dependent effects of acute bisphenol A exposure on hepatic lipid metabolism in zebrafish.
  1. J Clin Invest. 2025 Jun 02. pii: e184322. [Epub ahead of print]135(11):
    Social, microbial, and immune factors linking bacterial vaginosis and infectious diseases.
    Nicole M Gilbert, Luis A Ramirez Hernandez, Daniela Berman, Sydney Morrill, Pascal Gagneux, Amanda L Lewis.
      Bacterial vaginosis (BV) is a polymicrobial condition of the vaginal microbiota associated with a variety of sexually transmitted infections, infections of maternal and fetal tissues during pregnancy, and even some infections outside of the reproductive tract, including the urinary tract and mouth. BV has also been associated with conditions in which the body generates prominent inflammatory reactions to microbes, including infections of the cervix and other upper genital tract tissues. For reasons still not understood, BV is a highly recurrent and often difficult-to-treat condition, complicating attempts to prevent these associated infections. An additional layer of complexity arises from the increasing awareness that the presence of BV-associated bacteria in the vagina is not always symptomatic or associated with adverse outcomes. In this concise Review, we summarize and synthesize three groups of factors grounded in the literature that may be fueling the associations between BV and infection: (a) aspects of society and culture; (b) pathogens, virulence factors, and processes of microbial antagonism and synergy; and (c) host factors, such as genetics and immunity. Our goal is to understand what contexts and combinations of microbial, host, and social factors conspire to make BV virulent in some individuals but not others. Disrupting these patterns more systematically may achieve healthier outcomes.
    DOI:  https://doi.org/10.1172/JCI184322
  2. Am J Reprod Immunol. 2025 Jun;93(6): e70109
    Impact of Gut and Reproductive Tract Microbiota on Estrogen Metabolism in Endometriosis.
    ZeFeng Li, ZhaoFang Yin, WeiQi Chen, ZhiHong Wang.
       BACKGROUND: The incidence of endometriosis is rising, particularly among younger populations, yet current diagnostic and therapeutic approaches remain limited. This highlights the urgent need for novel diagnostic tools and effective treatments. Recent studies have shown that intestinal and reproductive tract bacterial dysbiosis is closely associated with the development of endometriosis and plays a key role in the regulation of estrogen metabolism.
    OBJECTIVES: This review aims to provide a comprehensive overview of the mechanisms of the microbiota's role in regulating estrogen levels and influencing the development and progression of endometriosis, providing important insights into the diagnosis and management of the disease.
    CONCLUSIONS: Microbial changes not only promote estrogen imbalance by regulating β-glucuronidase activity, but also respond to estrogen imbalance by affecting the expression of metabolites such as short-chain fatty acids and lipopolysaccharides. In addition, significant fluctuations in estrogen levels also affect the composition of the microbial community. Both factors jointly lead to changes in the immune microenvironment of endometriosis.
    Keywords:  endometriosis; estrogen metabolism; gut microbiome; immune inflammatory environment; microbial dysbiosis; reproductive tract infection
    DOI:  https://doi.org/10.1111/aji.70109
  3. iScience. 2025 May 16. 28(5): 112488
    Drug repurposing reveals posaconazole as a CYP11A1 inhibitor enhancing anti-tumor immunity.
    Jhuma Pramanik, Sanu Korumadathil Shaji, Megan Zaman, Bethany Brown, Baojie Zhang, Yumi Yamashita-Kanemaru, Natalie Z M Homer, Hosni A M Hussein, Qiuchen Zhao, Klaus Okkenhaug, Rahul Roychoudhuri, Abhik Mukhopadhyay, Bidesh Mahata.
      Steroid hormones regulate cell physiology and immune function, with dysregulated steroidogenesis promoting cancer progression by supporting tumor growth and suppressing anti-tumor immunity. Targeting CYP11A1, the first and rate-limiting enzyme in steroid biosynthesis, has shown promise in cancer therapy, but safe and effective inhibitors remain an unmet need. Undertaking in silico structure-based drug repurposing approach, we found posaconazole as an inhibitor of CYP11A1. The docking pose analysis showed that posaconazole can form multiple hydrogen bonds and hydrophobic interactions with the key residues at the binding site and the cofactor, stabilizing the protein-ligand complex. We validated its inhibition efficiency in cell-based assays. In a mouse model of lung metastasis, we demonstrated that posaconazole restricts metastasis by stimulating anti-tumor immunity. These findings highlight posaconazole's potential as a research tool to study steroidogenesis and as a candidate for further preclinical and clinical evaluation in pathologies associated with local steroidogenesis, such as steroidogenic tumors.
    Keywords:  Biological sciences; Cancer systems biology; Natural sciences; Pharmacology; Systems biology
    DOI:  https://doi.org/10.1016/j.isci.2025.112488
  4. BMC Pediatr. 2025 May 31. 25(1): 440
    Sex and age differences in cortisol levels during glucagon stimulation test in children.
    Camilla Borghammar, Johan Svensson, Anders Tidblad, Maria Elfving.
       BACKGROUND: Previous studies of glucagon stimulation test (GST) in children have shown variable results regarding the utility and reliability of the cortisol response to this test and its correlation with clinical parameters. The aim of this study was to assess cortisol levels at GST and to evaluate how clinical parameters, such as age, sex, pubertal status and Body Mass Index (BMI), correlate to cortisol levels in children.
    METHODS: A retrospective study of children evaluated for short stature with the GST. Cortisol, glucose and growth hormone (GH) levels at GST, as well as clinical parameters (age, sex, pubertal status, BMI), were collected from medical records. A peak cortisol of ≥ 450 nmol/L was used as a cut-off indicative of a sufficient response. Non-parametric tests were applied in the statistical analysis, and linear regression was used to examine factors affecting cortisol max at the GST.
    RESULTS: In total, 171 children were included; median age 7.8 years (1.0-18.0), 60 (35.1%) female, 23 (13.5%) pubertal. Of all children, 145 (84.8%) achieved a peak cortisol ≥ 450 nmol/L. There was a negative correlation between peak cortisol levels and age (Spearman's rho - 0.26, p = < 0.001). Peak cortisol levels were higher in females vs. males: 667.5 nmol/L (range 400-995) vs. 602 nmol/L (range 202-1008), p = 0.005. A higher number of boys than girls did not reach the cortisol cut-off value of 450 nmol/L (p = 0.022). The difference in maximum stimulated cortisol levels between the sexes remained after adjusting for age with a linear regression model (β (95% CI) 65.3 (15.9-114.6), p = 0.01).
    CONCLUSION: GST is a reliable test of the hypothalamic-pituitary-adrenal (HPA) axis in children. Girls and younger children had higher peak cortisol at GST. The results support a need for sex- and age-dependent reference values for cortisol.
    Keywords:  Child; Childhood; Cortisol; Glucagon test; Sex-differences
    DOI:  https://doi.org/10.1186/s12887-025-05784-5
  5. Cureus. 2025 Jun;17(6): e85270
    Understanding the Link Between Hormonal Changes and Gingival Health in Women: A Review.
    Sidra Tul Muntaha Jawed, Khadeeja Tul Kubra Jawed.
      Sex hormones, particularly estrogen and progesterone, undergo continuous fluctuations throughout a woman's life, beginning at puberty and extending through the menstrual cycle, pregnancy, and menopause. These hormonal variations significantly influence gingival health, leading to various periodontal conditions. During puberty, elevated levels of estrogen and progesterone enhance blood circulation to the gingival tissues, increasing their sensitivity to plaque and resulting in puberty gingivitis. This condition is characterized by gingival enlargement, redness, and bleeding. Throughout the menstrual cycle, hormonal fluctuations can cause menstrual gingivitis, presenting as inflamed and bleeding gums, typically occurring prior to menstruation and subsiding thereafter. Pregnancy induces substantial hormonal changes, with heightened estrogen and progesterone levels exacerbating gingival inflammation. This often leads to pregnancy gingivitis, marked by swelling, bleeding, and tenderness of the gums. In some cases, a localized overgrowth known as a pyogenic granuloma or "pregnancy tumor" may develop on the gingiva. The use of oral contraceptives, which alter hormonal levels, has been associated with increased gingival inflammation and exudate, similar to the effects observed during pregnancy. Menopause brings a significant decline in estrogen levels, leading to various oral health issues such as dry mouth (xerostomia), a burning sensation in the mouth, and an increased risk of osteoporosis affecting the alveolar bone supporting the teeth. These changes contribute to a heightened susceptibility to periodontal diseases in post-menopausal women. The influence of estrogen and progesterone on the immune response, oral microbial composition, bone density, and enzymes like collagenase plays a crucial role in modulating gingival inflammation and the risk of periodontal diseases. Understanding these hormonal impacts is essential for developing effective prevention and treatment strategies for maintaining optimal gingival health in women across different life stages.
    Keywords:  estrogen; gingival inflammation; hormonal changes; periodontal health; progesterone
    DOI:  https://doi.org/10.7759/cureus.85270
  6. Clin Exp Med. 2025 Jun 04. 25(1): 187
    The reciprocal regulation between autophagy and IL-22: implications for immunity and therapy.
    Yang Yu, Mingbiao Qiao, Jinbo Liu, Yuanbiao Guo, Yueshan Sun.
      Autophagy, a critical cellular process for maintaining homeostasis, involves the degradation and recycling of cellular components through double-membraned vesicles that are transported to lysosomes. This mechanism plays a pivotal role in the immune system by influencing cell fate decisions and functional differentiation. Emerging evidence indicates that autophagy significantly impacts the differentiation and function of T cells and group 3 innate lymphoid cell (ILC3), which are the primary producers of Interleukin-22 (IL-22). IL-22, a key cytokine involved in modulating immune responses and maintaining tissue integrity, is particularly important in combating inflammatory diseases, infections, and cancer. It exerts its effects through a signaling pathway that involves the IL-22R1 and IL-10R2 receptors. Studies have demonstrated that IL-22 can promote autophagy by activating the AMPK pathway and that its intervention can upregulate the expression of autophagy-related genes, underscoring its significant role in the regulation of autophagy. These findings reveal a complex relationship and bidirectional relationship between autophagy and IL-22, highlighting their multifaceted interactions under both physiological and pathological conditions. This review aims to provide a detailed exploration of the dynamic interplay between autophagy and IL-22, with a focus on their mutual regulatory mechanisms, functional significance, and potential for therapeutic interventions. By performing a comprehensive analysis, we sought to clarify the intricate cross talk between autophagy and IL-22, thereby advancing our understanding of their roles in cellular and immune homeostasis and their potential as targets for clinical interventions.
    Keywords:  Autophagy; Autophagy-IL-22 interplay; IL-22; Immune responses; Interleukin-22 (IL-22)
    DOI:  https://doi.org/10.1007/s10238-025-01695-y
  7. Am J Reprod Immunol. 2025 Jun;93(6): e70108
    Vaginal Microbiome Dominated by Lactobacillus Positively Impacts Clinical Pregnancy in Patients With Frozen Embryo Transfers.
    Addison W Alley, Paweł Łaniewski, Gabrielle T Bruno, Drew V Moffitt, Gayatri Arani, Leslie V Farland, Melissa M Herbst-Kralovetz.
       PROBLEM: There is evidence that the bacterial microbiome of the female reproductive tract affects fertility outcomes, but the findings are conflicting, and studies are lacking in racially and ethnically diverse populations.
    METHOD OF STUDY: In this prospective cohort study, vaginal swabs were collected from 87 female patients at time of frozen embryo transfer (FET) after oral estradiol preparation of the endometrium. The primary outcome was an ultrasound demonstrating a viable intrauterine pregnancy. 16s rRNA gene sequencing was performed on the swabs to compare the vaginal microbiome between those who achieved a viable pregnancy compared to those who did not.
    RESULTS: A total of 87 patients participated in the study, of whom 25% (22/87) reported a race other than White and 17% (15/87) identified as Hispanic. There were 55 patients who achieved clinical pregnancy. Patients who achieved pregnancy had a significantly higher prevalence of Lactobacillus-dominant profiles: 67% (37/55) compared with 41% (13/32) of the nonpregnant group (p = 0.024), with a relative risk of pregnancy of 1.52 [1.05, 2.20]. Nonpregnant patients exhibited more Enterobacteriacae and other opportunistic pathogens. Hispanic patients in the study cohort demonstrated decreased clinical pregnancy rates (p = 0.021) and lower Lactobacillus dominance (p = 0.01) compared to non-Hispanic White women.
    CONCLUSIONS: This study suggests that a vaginal microbiome predominated by Lactobacillus is associated with successful embryo implantation and early establishment of pregnancy after FET. Decreased Lactobacillus dominance may contribute to reproductive outcome disparities among Hispanic women. These findings support the consideration of the female reproductive microbiome in the evaluation and treatment of infertility.
    Keywords:  Lactobacillus; embryo transfer; fertility; in vitro fertilization; microbiome; pregnancy
    DOI:  https://doi.org/10.1111/aji.70108
  8. J Obstet Gynaecol Res. 2025 Jun;51(6): e16325
    Multicenter cohort study of the effect of Crinone® progesterone vaginal gel alone to prepare the endometrium for frozen-thawed blastocyst transfer in a hormone replacement cycle.
    Akiko Takashima, Yukihiro Shibui, Toshio Hamatani, Akihiko Suenaga, Yoshimitsu Kuwabara, Fuminori Kimura, Koji Nakagawa, Yusuke Fukuda, Shoji Tokunaga, Yukiko Katagiri.
       AIM: Progesterone has to be administered to prepare the endometrium for frozen-thawed blastocyst transfer (FBT) in a hormone replacement cycle (HRC). The objective of this study was to investigate the efficacy and safety of using Crinone® progesterone gel alone in HRC-FBT.
    METHODS: In this multicenter prospective study, HRC-FBT was performed with blastocysts with a Gardner's classification of 3BB or better, and application of 90 mg/day of vaginal gel (Crinone, Merck BioPharma, Tokyo) was started when the endometrial thickness reached 8 mm or more. The primary endpoint was the clinical pregnancy rate (CPR). Safety endpoints included genital bleeding and other adverse events. Recruitment started in May 2018.
    RESULTS: A total of 181 patients were enrolled, and 156 were included in the efficacy analysis. The overall CPR was 41.7% (65/156). In patients younger than 38 years (n = 113), the CPR was 48.7% (55/113), and in those aged 38 years or older (n = 43), it was 23.3% (10/43). The overall CPR was comparable to that observed in the Japan Society of Obstetrics and Gynecology ART2020 National Survey, which reported a pregnancy rate of 36.3% in frozen embryo transfer cycles. Adverse events such as light genital bleeding occurred before and after pregnancy in some patients, but at a low frequency (<10%).
    CONCLUSIONS: Use of Crinone progesterone vaginal gel alone is adequate in HRC-FBT and is not associated with any safety issues.
    Keywords:  frozen–thawed embryo transfer; hormone replacement; luteal phase support; pregnancy rate; progesterone
    DOI:  https://doi.org/10.1111/jog.16325
  9. J Cancer Res Clin Oncol. 2025 May 31. 151(6): 178
    Microbiome in prostate cancer: pathogenic mechanisms, multi-omics diagnostics, and synergistic therapies.
    Chengran Wang, Tianqi Dong, Xin'ao Rong, Yuce Yang, Jianhui Mou, Jiaqi Li, Jianli Ge, Xupeng Mu, Jinlan Jiang.
       BACKGROUND: Prostate cancer (PCa) is a leading cause of cancer-related deaths in men, with the microbiome emerging as a significant factor in its development and progression. Understanding the microbiome's role could provide new insights into PCa pathogenesis and treatment.
    OBJECTIVE: This review aims to explore the interactions between the microbiome and PCa, focusing on microbial imbalances and their effects on immune responses, inflammation, and hormone levels. It also discusses advanced research techniques and the potential for microbiome modulation in PCa management.
    METHODS: The review synthesizes current literature on the microbiome's role in PCa, highlighting differences in microbial composition between cancerous and healthy prostate tissues. It examines techniques such as high-throughput sequencing and metagenomics and explores the mechanisms through which the microbiome influences PCa.
    CONCLUSIONS: The review reveals substantial microbial differences in prostate tissues of PCa patients compared to healthy individuals, indicating a potential link between microbiome alterations and disease progression. It highlights the promise of microbiome-based strategies for diagnosis and treatment and underscores the need for further research into personalized, microbiome-centric approaches for PCa management.
    Keywords:  Diagnosis; Microbiome; Prognostic factors; Prostate cancer; Therapeutic targets
    DOI:  https://doi.org/10.1007/s00432-025-06187-w
  10. Reproduction. 2025 Jun 01. pii: REP-25-0044. [Epub ahead of print]
    Divergence in the Sow Vaginal Microbiota is Associated with Fertility.
    Lauren Fletcher, Xiaoshu Zhan, Yashu Song, Julang Li.
      There is a need for reliable and effective biomarkers of female fertility and reproductive potential in the pork industry as current selection protocols are not keeping up with the rate of improvement for other production-related traits. This study aimed to investigate the vaginal microbiota composition between sows of differing fertility status and identify candidate vaginal microbial biomarkers of sow fertility. The vaginal microbiota of high reproductive performance sows (HRP, n=52) with number of piglets born alive ≥ 13 and infertile sows (INF, n=23), that remained nonpregnant after two consecutive rounds of artificial insemination were investigated. Sequencing results revealed significantly different (p < 0.05) beta diversity at the genus level between HRP and INF vaginal microbiota communities. Accordingly, the composition of the vaginal microbiota diverged between HRP and INF sows, with INF sows having increased (p < 0.05) relative abundance of Lachnospiraceae XPB1014 group and HRP sows having increased (p < 0.05) relative abundance of Aerococcus and Staphylococcus at the genus level. Forty-two genera were selected as candidate biomarkers of sow fertility via partial least squares discriminant analysis (PLS-DA) and recursive feature elimination (RFE). The support-vector machine (SVM) model classified sow fertility with 93.3% accuracy, supporting potential industry application to improve upon current methods for selection and recruitment in the breeding herd. Future investigations should validate the candidate vaginal microbiota biomarkers in a large, independent population of sows and gilts to evaluate their application for predicting future reproductive performance and assess their true industry applicability.
    DOI:  https://doi.org/10.1530/REP-25-0044
  11. Mol Cancer. 2025 Jun 03. 24(1): 161
    Reprogrammed immuno-metabolic environment of cancer: the driving force of ferroptosis resistance.
    Sramana Bhowmick, Saptak Banerjee, Viji Shridhar, Susmita Mondal.
      Ferroptosis, the non-apoptotic, iron-dependent form of cell death is an unavoidable outcome and byproduct of cellular metabolism. Reactive oxygen species generation during metabolic activities transcends to Fe2+-induced lipid peroxidation, leading to ferroptosis. Cancer cells being highly metabolic are more prone to ferroptosis. However, their neoplastic nature enables them to bypass ferroptosis and become ferroptosis-resistant. The capability of cancer cells to reprogram its metabolic activities is one of its finest abilities to abort oxidative damage, and hence ferroptosis. Moreover, the reprogrammed metabolism of cancer cells, also associates with the radical trapping antioxidant systems to enhance the scavenging of ferroptosis and thereby tumor progression. Additionally, the TME, which is an inevitable part and regulator of carcinogenesis, presents an intricate cooperation with tumor metabolism to build an immuno-metabolic environment to regulate the sustenance of cell proliferation and survival. This review focuses on the current understanding of ferroptosis in carcinogenesis and its resistance acquired by cancer cells via several modulators including the radical trapping antioxidant systems, the reprogrammed metabolism, the TME, and intertwined role of cancer metabolism and tumor immunity. The reprogrammed metabolism section further comprehends the functional role of lipids, iron and glucose metabolism against ferroptosis defense separately. The affiliation of TME in ferroptosis regulation is further sectioned with reference to different immune cells present within the TME such as tumor-associated macrophages, tumor-infiltrating neutrophils, myeloid-derived suppressor cells, T-cells, natural killer cells, dendritic cells, and B-cells, modifying the TME in both pro and anti-tumorigenic manner. Subsequently, this review also discusses the convergence of immuno-metabolic environment in ferroptosis regulation, and eventually brings up research gaps in this context providing consequential and significant questions to explore for better understanding of the immuno-metabolic environment's role in driving ferroptosis resistance for anti-cancer treatment progress.
    Keywords:  Ferroptosis; Ferroptosis resistance; Metabolic reprogramming; Reprogrammed immune metabolic environment; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12943-025-02337-3
  12. Acta Diabetol. 2025 Jun 05.
    Crosstalk of immunity and metabolism: interaction of toll-like receptors (TLRs) and gut microbiota.
    Shabana, Saleem Ullah Shahid, Uzma Irfan, Sumreen Hayat, Sumbal Sarwar.
      The human gut is the largest interface between the external environment and the human body. The gut immune system should, therefore, be able to differentiate between the normal nonpathogenic residents of the gut and any pathogenic invaders. This differentiation is based on the tiny molecular differences on the cell surfaces of the microorganisms. The first interaction between the pathogen and the immune system is thus crucial. This sensing by the immune system is done by a family of pattern recognition receptors (PRRs), among which the most important are the toll-like receptors (TLRs). The distribution of TLRs in the different areas of gastrointestinal tract (GIT)c depends on the type of commensal residents of that area. The interaction between gut microbiota and TLRs on one hand restricts the colonization of particular microbes to a particular area and on the other hand, dictates the type of TLRs distributed in a particular gut location. This interaction promotes tolerance to the normal residents, but the same time enables the gut associated lymphoid tissue to be able to detect any foreign and potentially pathogenic invaders. The numbers and polarization of the underlying populations of macrophages and dendritic cells beneath the Paneth and M-cells depends upon the trophic factors released by the intestinal epithelial cells as a result of signaling through TLRs. The interaction between these two players is not only immune related, but also has many metabolic consequences. The link between inflammation and many metabolic diseases has been consistently reported. The role of TLRs in the metabolic reprogramming of immune cells is crucial which facilitates the conservation of metabolic energy to be harnessed for immune functions. The knowledge on the TLR-microbiota interaction, its role in immune and metabolic functions, and the results of manipulations with this interaction are the subject of this review.
    Keywords:  Immune system; Inflammation; Lymphoid tissue; Pattern recognition receptors; Toll-like receptors
    DOI:  https://doi.org/10.1007/s00592-025-02532-0
  13. Cell Rep. 2025 May 30. pii: S2211-1247(25)00525-X. [Epub ahead of print]44(6): 115754
    Molecular basis of autoimmune disease protection by MDA5 variants.
    Rahul Singh, Joe D Joiner, Alba Herrero Del Valle, Marleen Zwaagstra, Ida Jobe, Brian J Ferguson, Frank J M van Kuppeveld, Yorgo Modis.
      MDA5 recognizes double-stranded RNA (dsRNA) from viruses and retroelements. Cooperative filament formation and ATP-dependent proofreading confer MDA5 with the necessary sensitivity and specificity for dsRNA. Many MDA5 genetic variants are associated with protection from autoimmune disease while increasing the risk of infection and chronic inflammation. How these variants affect RNA sensing remains unclear. Here, we determine the consequences of autoimmune-protective variants on the molecular structure and activities of MDA5. Rare variants E627∗ and I923V reduce the interferon response to picornavirus infection. E627∗ does not bind RNA. I923V is ATPase hyperactive, causing premature dissociation from dsRNA. Cryoelectron microscopy (cryo-EM) structures of MDA5 I923V bound to dsRNA at different stages of ATP hydrolysis reveal smaller RNA binding interfaces, leading to excessive proofreading activity. Variants R843H and T946A, which are genetically linked and cause mild phenotypes, did not affect cytokine induction, suggesting an indirect disease mechanism. In conclusion, autoimmune-protective MDA5 variants dampen MDA5-dependent signaling via multiple mechanisms.
    Keywords:  ATPase; CP: Immunology; RIG-I-like receptor (RLR); RNA helicase; RNA sensing; autoimmune disease mutations; double-stranded RNA (dsRNA); fitness tradeoff; human genetic variants; innate immunity; molecular mechanism of disease
    DOI:  https://doi.org/10.1016/j.celrep.2025.115754
  14. Ecotoxicol Environ Saf. 2025 May 30. pii: S0147-6513(25)00764-X. [Epub ahead of print]300 118428
    Integrated lipidomics and metabolomics approach to assess sex-dependent effects of acute bisphenol A exposure on hepatic lipid metabolism in zebrafish.
    Yoonjeong Jeon, Sung-Gil Choi, Won Noh, Jong-Wook Song, Ji-Woo Yu, Min-Ho Song, Ji-Ho Lee, Jong-Su Seo, Jong-Hwan Kim.
      High concentrations of bisphenol A (BPA), a typical endocrine disruptor, have been widely found in rivers and oceans due to its extensive use in polymer production. Direct exposure to BPA in the aquatic environment is known to have toxic effects including their immune responses, neuroendocrine and reproductive systems and development on aquatic organisms. BPA has various adverse effects associated with the lipid metabolism of fish. However, there are limited studies on the specific mechanisms on sex-dependent differences in hepatic lipid metabolism in BPA-exposed fish. Therefore, we performed comparative lipid profiling by UPLC-MS/MS and metabolite profiling by GC-MS/MS in male and female zebrafish livers during uptake and depuration of BPA. BPA exposure led to similar changes in various hepatic lipids in male and female zebrafish, but several lipids including triacylglycerols were affected differently in a sex- and exposure duration-dependent manner. There were also sex-dependent responses of hepatic metabolites such as GABA, alanine, glucose, sarcosine, and allantoin, consistent with the trends in changes in lipids in response to BPA exposure in male and female zebrafish. Overall, our study identified sex-dependent differences in specific lipids and metabolites in the liver of zebrafish exposed to BPA. These findings might provide a novel reference for understanding the metabolic toxic effects of BPA and the pathways involved in these effects in aquatic organisms.
    Keywords:  Bisphenol A; Lipidomics; Metabolomics; Sex differences; Zebrafish
    DOI:  https://doi.org/10.1016/j.ecoenv.2025.118428
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