bims-simsho 2025-08-24 papers

bims-simsho

Biomed News

on Systems immunology and sex hormones

Issue of 2025–08–24
fifteen papers selected by
Chun-Chi Chang, Lunds universitet

The Ability of Neonatal Mice to Develop Immunity to Mycobacterium tuberculosis Shows Sex Differences, with Females Displaying Evidence of an Enhanced Immune Response.
Sex differences and the role of estrogens in the immunological underpinnings of Alzheimer's disease.
Correlation between SARS-CoV-2-specific antibody titers and the hormones DHEA, cortisol, testosterone, and progesterone.
Adolescent PCOS and metabolic health: An analysis of fat, muscle, and hormones.
Single-cell analysis of follicular fluid reveals dysregulation of ovulatory immune function in PCOS patients undergoing ovarian stimulation.
Precision targeting of androgen receptor-ferroptosis crosstalk in prostate cancer: From mechanisms to therapeutic strategies.
A systems approach for elucidating the role of the microbiome in epigenetic cellular memory.
Sex Hormone Androgen Elevates Blood Pressure Through Gut Microbiota-TMAO Pathway.
Association between repeat number polymorphisms of sex hormone-related genes and gender phenotype variations in university students.
Interplay between the host genome, autoimmune disease and infection.
Genetic and Epigenetic Reprogramming of Transposable Elements Drives ecDNA-Mediated Metastatic Prostate Cancer.
Effect of nutritional intervention combined with vitamin D on glucose metabolism, sex hormones and inflammatory factors in patients with polycystic ovary syndrome.
DNA methylation patterns associated with prior tuberculosis infection in people with HIV.
Immuno-metabolic diseases and therapeutics: molecular mechanisms via inflammasome signaling.
Mucosal immunity and vaccination strategies: current insights and future perspectives.

J Cell Immunol. 2025 ;7(2): 52-63

The Ability of Neonatal Mice to Develop Immunity to Mycobacterium tuberculosis Shows Sex Differences, with Females Displaying Evidence of an Enhanced Immune Response.

Mrinal K Ghosh, Ameae M Walker.

  Using four core genotypes (FCG) mice, we have previously shown a larger number of CD4+ and CD8+ T cells in the spleens of female mice, a sex difference that develops by postnatal day 7 and is retained through adulthood. This difference in splenic T cell number is a consequence of reduced thymic egress and reduced splenic seeding in male mice, caused in part by the male-specific perinatal surge of testosterone, and in part by Sry, which is overexpressed in this model. Here, we used the background strain for FCG mice (C57BL/6J) to ask whether sex influenced actual immunity in the postnatal period. Pups were immunized on postpartum days 1 or 3 with Mycobacterium tuberculosis (Mtb), challenged on day 7 with Mtb purified protein derivative (PPD), and sacrificed on day 8. Subsequent ex vivo challenges of splenocytes showed PPD-stimulated CD8+ responses (increased CD8+, increased CD8+CD44hi, decreased CD8+CD44hiCD127-/lo) but no differences between males and females. However, when CD8+ T cells were analyzed for IFN-γ and IL-2 production, although there was no sex difference in mono-functional IFN-γ+ (100%) or IL-2+ (67%), only females (0% of males and 42% of females) produced bi-functional (IFN-γ+IL-2+) cells. Ex vivo PPD-stimulated responses of other relevant cells from the spleen showed no sex differences in dendritic cells (CD11c+CD86+IL-6+) but females had more (3-fold) IL-6-producing macrophages (F4/80+CD86+IL-6+) and reduced T regulatory cells (CD4+CD25+Foxp3+). We conclude that some sex differences in immunity are evident at one week of age in Mtb immunized mouse pups, with females exhibiting qualitatively superior Mtb-specific immune responses.

Keywords:  Bi-functional CD8+ T cells; Improvement in neonatal immunity; Male bias in TB susceptibility; Perinatal testosterone surge; Sex differences in neonatal immunity; Tuberculosis

DOI:  https://doi.org/10.33696/immunology.7.225
Alzheimers Dement (N Y). 2025 Jul-Sep;11(3):11(3): e70139

Sex differences and the role of estrogens in the immunological underpinnings of Alzheimer's disease.

Brittani R Price, Keenan A Walker, Jaclyn M Eissman, Vidyani Suryadevara, Lindsey N Sime, Timothy J Hohman, Marcia N Gordon.

  Alzheimer's disease (AD) affects women more frequently and more severely than men, but the biological mechanisms underlying these sex differences remain poorly understood. This review integrates recent findings from neuroscience, immunology, endocrinology, and genetics to explore how sex steroid hormones, particularly estrogen, shape neuroimmune responses and influence AD risk. We highlight the pivotal roles of microglia and astrocytes, whose inflammatory and neuroprotective actions are modulated by hormonal fluctuations across the female lifespan, including pregnancy, menopause, and menopausal hormone replacement therapy. Key genetic risk factors, such as apolipoprotein E ε4, show sex-specific effects on glial activation, tau pathology, and cognitive decline. Furthermore, life-stage transitions, especially menopause, intersect with changes in brain metabolism, immune signaling, and epigenetic regulation, increasing susceptibility to neurodegeneration in women. We propose a framework for sex-aware, personalized approaches to AD prevention and treatment. By integrating hormone-immune interactions with genetic and glial biology, this review emphasizes the critical need for sex-specific models in AD research.
Highlights: Women develop greater tauopathy, with more cognitive and clinical consequences in Alzheimer's disease (AD).Glial activation is adapted by estrogens to shape vulnerability or resilience to AD.Sex differences in innate and adaptive immunity could contribute to AD progression.Effects of menopausal hormone therapy on immunity in AD remain understudied.Future studies to explore sex differences in immune function during AD are needed.

Keywords:  adaptive immunity; apolipoprotein E; astrocytes; cognitive decline; estradiol; estrogen; innate immunity; menopause; microglia; neuroinflammation

DOI:  https://doi.org/10.1002/trc2.70139
Front Immunol. 2025 ;16 1560623

Correlation between SARS-CoV-2-specific antibody titers and the hormones DHEA, cortisol, testosterone, and progesterone.

Tanja Karl, Anja Schuster, Janne Cadamuro, Gertie Janneke Oostingh.

  Hormones, such as DHEA, cortisol, testosterone, and progesterone play an important part in the regulation of the human immune system. However, the exact role of endocrine factors in the production of antibodies, in this case SARS-CoV-2-specific antibodies, remains poorly understood. We investigated the association between hormone levels and SARS-CoV-2 spike-protein-specific IgG antibody titers in a large, diverse cohort of 861 vaccinated as well as vaccinated plus COVID-19 recovered individuals. We observed negative correlations between cortisol, progesterone, testosterone (in males), and SARS-CoV-2-specific antibody levels. In contrast, a positive correlation was found between DHEA and antibody titers in vaccinated males. These hormone-antibody relationships exhibited important sex-specific differences. Our findings demonstrate that hormonal factors are associated with modulating the antibody response to SARS-CoV-2, with implications for personalized approaches to vaccination and treatment. Furthermore, the wide variability in hormone levels within the healthy population also suggests the potential value of incorporating endocrine assessments into COVID-19 risk profiling. Further research is needed to fully elucidate the mechanistic underpinnings of these hormone-antibody relationships and explore their broader clinical applications in the context of the ongoing COVID-19 endemic.

Keywords:  COVID-19; DHEA; SARS-CoV-2-specific antibodies; cortisol; hormones; personalized medicine; progesterone; testosterone

DOI:  https://doi.org/10.3389/fimmu.2025.1560623
Eur J Obstet Gynecol Reprod Biol. 2025 Aug 11. pii: S0301-2115(25)00924-8. [Epub ahead of print]314 114648

Adolescent PCOS and metabolic health: An analysis of fat, muscle, and hormones.

Leyla Kara, Dilek Cicek, Emre Sarikaya, Ebru Gok, Ugur Berber, Ulku Gul Siraz, Mustafa Kendirci, Nihal Hatipoglu.

   OBJECTIVE: This study aimed to evaluate anthropometric, metabolic, hormonal, and body composition characteristics in adolescents with polycystic ovary syndrome (PCOS) compared to healthy controls, with further analyses by metabolic syndrome (MetS) status and body mass index (BMI) categories.
METHODS: A total of 69 adolescents with PCOS and 63 age-matched healthy controls were included. Participants underwent assessments of anthropometric measures, metabolic and hormonal profiles, and body composition via bioelectrical impedance analysis. Subgroup analyses were performed according to BMI (<30 and ≥ 30 kg/m2) and MetS status.
RESULTS: There were no significant differences in age, BMI, or waist circumference between groups. However, adolescents with PCOS had significantly higher systolic and diastolic blood pressure (p = 0.013 and p = 0.022), and elevated androgen levels including total testosterone (p < 0.001), free androgen index (p < 0.001), and DHEA-SO4 (p < 0.001), with lower SHBG levels (p = 0.007). Metabolic parameters such as fasting glucose, triglycerides, and HDL cholesterol showed no significant differences.Body composition measures-including fat mass, muscle mass indices, and trunk fat mass-were comparable between PCOS and control groups. Subgroup analysis revealed that lean adolescents with PCOS exhibited higher androgen levels and increased skeletal muscle indices compared to lean controls. In contrast, obese adolescents with PCOS showed a significantly higher prevalence of MetS compared to non-obese counterparts (p = 0.002). Correlation analyses showed that waist circumference strongly correlated with fat mass, percent body fat, and inversely with SHBG and HDL-C in both groups. FAI was positively associated with adiposity measures and negatively with SHBG. In the PCOS group, HDL-C was more consistently and negatively associated with adiposity and hormonal markers, indicating early lipid metabolism disturbances.
CONCLUSION: Adolescents with PCOS exhibit early cardiovascular and hormonal alterations, particularly elevated blood pressure and androgen excess, even in the absence of major body composition changes. Obesity further amplifies metabolic risk, as evidenced by the higher MetS prevalence among obese PCOS adolescents. Comprehensive metabolic and hormonal evaluation, beyond anthropometric measures, is essential for early detection and management of cardiometabolic risks in adolescents with PCOS.

Keywords:  Adolescents Cardiovascular Risk; Androgen Excess; Body composition; Fat mass; Metabolic Syndrome (MetS); Muscle mass; Obesity; Polycystic Ovary Syndrome (PCOS)

DOI:  https://doi.org/10.1016/j.ejogrb.2025.114648
medRxiv. 2025 Aug 12. pii: 2025.08.11.25333027. [Epub ahead of print]

Single-cell analysis of follicular fluid reveals dysregulation of ovulatory immune function in PCOS patients undergoing ovarian stimulation.

Andrea K Wegrzynowicz, Soma Banerjee, Emily Grimes, Riley Huddleston, Fernanda Leyva Jaimes, Laura G Cooney, Aleksandar K Stanic.

Polycystic ovary syndrome is the most common endocrine condition in women and anovulatory cause of female infertility. While a pro-inflammatory cytokines and leukocyte bias in systemic circulation is well-documented in PCOS, it is not known how this inflammation extends to or affects the ovary. Additionally, the relationship between ovulation and inflammation in PCOS is not well-defined. We hypothesize that the ovarian follicular immune environment in PCOS is uniquely dysregulated, and that resolving anovulation through ovulation induction is not sufficient to alleviate this dysregulation. Using single-cell RNA and surface protein analysis of peripheral blood and follicular fluid from patients undergoing in vitro fertilization, we discovered that both control and PCOS follicles were immunologically distinct from circulation. At a systemic level, we find that ovulation induction in PCOS does not alleviate systemic inflammation. In contrast, while healthy control ovaries experienced acute immune-directed ovulatory signaling, PCOS ovarian follicles were deficient in key pro-ovulatory cell to cell communication, and displayed instead a chronic low-grade inflammatory state with fibrotic features. Taken together, a picture emerges where acute ovulation demonstrates a well-ordered series of follicle-specific immune information flows, which are disrupted and replaced by low grade chronic inflammation in the PCOS follicle.

DOI: https://doi.org/10.1101/2025.08.11.25333027
Pharmacol Res. 2025 Aug 15. pii: S1043-6618(25)00340-8. [Epub ahead of print]219 107915

Precision targeting of androgen receptor-ferroptosis crosstalk in prostate cancer: From mechanisms to therapeutic strategies.

Dongfang Lv, Yankang Shi, Luan Kou, Denglu Zhang, Yanxia Guo, Shengtian Zhao.

  Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, has emerged as a promising vulnerability in cancer therapy. In prostate cancer (PCa), androgen receptor (AR) signaling remains a central oncogenic driver, with androgen deprivation therapy (ADT) as the standard of care. Emerging evidence suggests a bidirectional interaction between ferroptosis and AR signaling: ADT may sensitize cancer cells to ferroptosis by disrupting iron and lipid homeostasis, while ferroptosis-induced oxidative stress may in turn attenuate AR transcriptional activity. This review synthesizes current mechanistic insights into this interplay, highlighting key AR-regulated mediators of ferroptosis resistance, including MBOAT2, SLC7A11, and PEX10. We also discuss the therapeutic potential of dual-function agents, such as darolutamide and erastin, which simultaneously inhibit AR activity and induce ferroptosis, representing a novel strategy for treating castration-resistant prostate cancer (CRPC). Finally, we propose that combining ferroptosis inducers with AR-targeted therapies, guided by metabolic and redox biomarkers, may overcome therapeutic resistance and enable precision oncology approaches for advanced PCa.

Keywords:  Androgen deprivation therapy; Androgen receptor signaling; Dual-targeted therapy; Ferroptosis; Precision oncology; Prostate cancer

DOI:  https://doi.org/10.1016/j.phrs.2025.107915
mSystems. 2025 Aug 18. e0018525

A systems approach for elucidating the role of the microbiome in epigenetic cellular memory.

Jacob W Pederson, Aleksandra Nita-Lazar.

  The microbiome plays an essential role in the development of the immune system. Both the immune system and microbiome dynamically respond to internal and external cues, and dysregulation of either of these systems can lead to disease pathology. Separate from the adaptive immune system, the innate immune system retains a memory of inflammatory events that determine the quality of future immune responses. The phenomenon is characterized by epigenetic modifications that lead to immunosuppressive or hyperinflammatory cell phenotypes, collectively designated as epigenetic cellular memory. It remains unclear whether and how the microbiome influences epigenetic cellular memory phenotypes to promote immunopathology and chronic disease. Inflammatory signals from the microbiota regulate hematopoiesis and systemic immunity through the production of immunomodulatory ligands and activation of circulating immune cells; however, few studies have directly implicated these mechanisms in the development of epigenetic cellular memory. We posit that a multi-omic systems approach is well-suited to elucidating the complex factors mediating the microbiome's contribution to this phenomenon. By measuring responses to exogenous influences through multi-omic technologies, it will be possible to identify the regulatory axis that next-generation therapies should target to reverse immunopathology. As chronic inflammatory disorders are on the rise, it is imperative that future therapies leverage both dietary and pharmacological interventions to promote self-reinforcing homeostatic immunity by targeting the mechanisms of epigenetic cellular memory.

Keywords:  immune memory; innate immunity; microbiome; systems biology

DOI:  https://doi.org/10.1128/msystems.00185-25
Hypertension. 2025 Aug 20.

Sex Hormone Androgen Elevates Blood Pressure Through Gut Microbiota-TMAO Pathway.

Ying Li, Hong-Li Jiang, Lei Chen, Jia-Yue Yu, Sachin Aryal, Ya-Nan Gao, Ying-Bao Zhu, Wen-Fang Lu, Zhi-Ming Dai, Li-Li Huang, Qi Liu, Hua Liu, Li-Min Wei, Xue Zhao, Xiao-Min Liu, Juan Bai, Xiao-Lian Shi, Qing Su, Meng-Lu Xu, Ishan Manandhar, Pritam Bardhan, Ya-Nan Wang, Ting Yao, Bina Joe, Tao Yang, Hong-Bao Li.

   BACKGROUND: Hypertension is a leading risk factor for all-cause mortality worldwide, affecting ≈1.3 billion people. Imbalanced gut microbiota contributes to blood pressure elevation. We recently reported sex differences in the responses of gut microbiota to environmental stimuli, such as salt, with male gut microbiota being more vulnerable to induce high blood pressure than female microbiota. In this study, we investigated the mechanisms by which gut microbiota regulate blood pressure in a sex-dependent manner.
METHODS: Antibiotic treatment, gonadectomy, sex hormone replenishment, and treatment with trimethylamine N-oxide or its blocker were performed in male and female spontaneously hypertensive rats.
RESULTS: We observed sex differences in gut microbiota composition and sex-specific blood pressure responses to antibiotic treatment in pubertal spontaneously hypertensive rats. In gonadectomized rats treated with sex hormones, we found that the male sex hormone dihydrotestosterone elevated blood pressure, reshaped gut microbiota, and increased levels of microbiota-derived metabolites, trimethylamine and treatment with trimethylamine N-oxide. The accumulation of treatment with trimethylamine N-oxide in plasma and the paraventricular nucleus of the hypothalamus was associated with inflammation and sympathetic activation.
CONCLUSIONS: These findings underscore the mechanistic role of dihydrotestosterone in gut microbiota-mediated sex-specific blood pressure regulation and suggest that targeting the gut microbiota-treatment with trimethylamine N-oxide pathway may provide new therapeutic strategies for male hypertension.

Keywords:  TMAO; dihydrotestosterone; gut-brain axis; hypertension; sex difference

DOI:  https://doi.org/10.1161/HYPERTENSIONAHA.125.25052
Sex Med. 2025 Aug;13(4): qfaf060

Association between repeat number polymorphisms of sex hormone-related genes and gender phenotype variations in university students.

Mizuho Igarashi, Yuko Katoh-Fukui, Atsushi Hattori, Kyongsun Pak, Shoko Sasaki, Maki Fukami.

   Background: Although common repeat number polymorphisms in 3 hormone-related genes (AR, CYP19A1, and ESR2) have been implicated in the variations in several sexually dimorphic phenotypes, their contributions to the variations in gender identity (GI) and sexual orientation (SO) remain to be clarified.
Aim: To clarify the possible association between the repeat number polymorphisms and gender phenotype variations in the general population.
Methods: We used paper-based questionnaires to select 80 individuals with atypical gender phenotypes (the case group) and 114 control individuals (the control group) from 736 university students. The case group was further divided into two subgroups: one consisted of individuals with low GI scores (the atypical GI subgroup), and the other consisted of individuals with non-heterosexual orientation (the atypical SO subgroup). Repeat numbers of the longer and shorter alleles in each participant (Alleles 1 and 2) were examined through microsatellite analysis. Repeat numbers of AR in females were adjusted for the X chromosome inactivation status.
Outcomes: We examined the statistical differences in the repeat numbers between the case and control groups, and between each subgroup and the control group.
Results: The overall differences between the case and control groups and between each subgroup and the control group were small. However, the repeat numbers of AR in males of the case group were larger than those of the control group (P = 0.049), and the repeat numbers of ESR2 Allele 1 were larger in males of the atypical GI subgroup than in those of the control group (P = 0.046). In addition, females in the atypical SO subgroup had smaller repeat numbers of CYP19A1 Allele 2 than control females (P = 0.011).
Clinical Implications: These results indicate the complex genetic basis of gender phenotype variations.
Strengths & Limitations: This is the first study that addresses the possible association between common polymorphisms in hormone-related genes and gender phenotypes in the general population. Given the small number of our subjects and the modest differences in the repeat numbers between the case and control groups, our results await further validation.
Conclusion: The results indicate that the contribution of repeat number polymorphisms of the 3 genes to gender phenotype variations in the general population is small, although the repeat numbers of AR and ESR2 are potentially associated with atypical gender phenotypes in males.

Keywords:  androgen; estrogen; gender identity; polymorphism; sex hormone receptor; sexual orientation

DOI:  https://doi.org/10.1093/sexmed/qfaf060
Adv Genet. 2025 ;pii: S0065-2660(25)00006-9. [Epub ahead of print]114 101-139

Interplay between the host genome, autoimmune disease and infection.

María Isabel San-Martín, África Sanchiz, Nicolas Navasa.

  Throughout human history, pathogens have exerted great pressure on human genome that have defined susceptibility to both infectious and autoimmune diseases. This is possible because both type of conditions share susceptibility loci. The emergence of novel technologies that improves the genome analysis has greatly enhanced our ability to characterize in deeper the genetic architecture of human susceptibility to infectious diseases and autoimmune conditions. These genetic data sets identify outstanding informative overlaps that point to genetic modulation of immune function and inflammatory responses that affects both types of conditions. In this work, we revised single nucleotide polymorphisms and other genetic variations shared between these two categories of disease.

Keywords:  Antagonistic pleiotropy; Autoimmune disease; Disease susceptibility; Immunity; Infectious disease; Natural selection; Single nucleotide polymorphism

DOI:  https://doi.org/10.1016/bs.adgen.2025.02.006
bioRxiv. 2025 Aug 12. pii: 2025.08.08.668693. [Epub ahead of print]

Genetic and Epigenetic Reprogramming of Transposable Elements Drives ecDNA-Mediated Metastatic Prostate Cancer.

Lisanne Mout, Thaidy Moreno-Rodriguez, Giacomo Grillo, Ankita Nand, Tina Keshavarzian, Shalini Bahl, Komaldeep Kang, Matthew Bootsma, Emma Minnee, Stanley Zhou, Kathleen H Burns, Eva Corey, Peter Nelson, Scott M Dehm, Shuang G Zhao, Wilbert Zwart, Felix Feng, David Quigley, Mathieu Lupien.

Extrachromosomal DNAs (ecDNAs), which replicate and segregate in a non-Mendelian manner, serve as vectors for accelerated tumor evolution. By integrating chromatin accessibility, whole-genome sequencing, and Hi-C-based genome topology data from a cohort of metastatic Castration-Resistant Prostate Cancer (mCRPC) cases, we show that epigenetically activated repeat DNA, amplified in ecDNAs, drive oncogene overexpression. Specifically, we identify a subgroup of mCRPCs (20%) characterized by clusters of accessible LINE1 repeat DNA elements flanking the androgen receptor (AR) gene. These LINE1 elements are co-amplified with AR and provide binding sites for prostate-lineage transcription factors, including AR, FOXA1 and HOXB13. Accessible LINE1 elements establish novel 3D chromatin interactions with the AR gene, forging a new regulatory plexus driving AR overexpression and confers resistance to androgen signaling inhibitors. Our findings indicate how tumor evolution is driven by the convergence of genetic and epigenetic alterations on repeat DNA, activating and amplifying them to allow oncogene overexpression.
Statement of significance: We show how tumor evolution is driven by the convergence of genetic and epigenetic alterations on repeat DNA elements, resulting in their activation as regulatory elements and co-amplification in ecDNAs with oncogenes in mCRPC.

DOI: https://doi.org/10.1101/2025.08.08.668693
J Med Biochem. 2025 Jun 13. 44(3): 595-602

Effect of nutritional intervention combined with vitamin D on glucose metabolism, sex hormones and inflammatory factors in patients with polycystic ovary syndrome.

Xinqin Kang, Lin Liu.

   Background: Polycystic ovary syndrome is a very common endocrine and metabolic disease in clinical practice. Most polycystic ovary syndrome patients are complicated with obesity, a condition associated with an elevated risk of long-term complications such as diabetes, hypertension, and endometrial cancer, seriously threatening the health of patients. The best way to treat this disease is to use drugs to promote ovulation, adjust the menstrual period, and restore pregnancy. However, the drugs used to treat obesity and polycystic ovary syndrome usually have entirely opposite effects, resulting in unsatisfactory rehabilitation.
Methods: This study selected 102 obese or overweight PCOS patients treated in our hospital from July 2022 to July 2024 as the research subjects. Sex hormones: The levels of prolactin (PRL), testosterone (T), follicle-stimulating hormone (FSH), and luteinising hormone (LH) were measured by electrochemiluminescence. Inflammation: C-reactive protein (CRP), white blood cell count (WBC), and procalcitonin (PCT) were examined by an automated blood cell counter. 46 (control group) of the 102 were treated with a conventional treatment scheme, and the other 56 (experimental group) were intervened by nutritional intervention combined with vitamin D based on conventional treatment.
Results: Both groups showed reductions in sex hormone levels after treatment, with the PRL, T, LH, and FSH in the experimental group being (5.12±0.51) ng/mL, (1.22±0.32) ng/mL, (9.14±1.61) mIU/mL, and (5.01±0.42) mIU/mL, respectively, all of which were lower compared with the control group (P<0.05).
Conclusions: In this study, we intervened obese polycystic ovary syndrome patients with nutritional or conventional intervention and found that compared with conventional treatment, the posture, blood glucose metabolism, and lipid function of the patients who received nutritional intervention were more significantly metabolised, and the levels of inflammatory factors were more effectively inhibited, indicating the high clinical application value of nutritional intervention in obese polycystic ovary syndrome.

Keywords:  endocrine; inflammatory response; nutritional interventions; nutritional status; polycystic ovary syndrome

DOI:  https://doi.org/10.5937/jomb0-53948
Sci Rep. 2025 Aug 19. 15(1): 30349

DNA methylation patterns associated with prior tuberculosis infection in people with HIV.

Joseph Baruch Baluku, Sharon Namiiro, Daphine Kigongo Zawedde, Brenda Namanda, Hakiimu Kawalya, Irene Najjingo, Waiswa Geoffrey, Nixon Niyonzima, Naghib Bogere, Edwin Nuwagira, Joshua Rhein, Nick Jones, Christian Kraef, Megan Shaughnessy, Arohi Chauhan, Immaculate Nankya, Sayoki Mfinanga, Stanton Gerson, Bruce Kirenga.

  Mechanisms by which prior tuberculosis (TB) increases long-term risk for cancer, cardiovascular, and neurological disorders remain unclear, particularly in people with HIV (PWH). This study investigated DNA methylation (DNAm) patterns and associated pathways in PWH with and without prior TB infection. DNAm was analyzed in blood samples from 30 PWH (10 with prior latent TB infection [LTBI], 10 with previous successfully treated active TB, and 10 with no TB) using the Illumina MethylationEPIC BeadChip covering over 850,000 CpG sites. Epigenetic age was estimated, and age acceleration was calculated. Differentially methylated CpGs (dmCpGs) and regions (DMRs) were identified, and functional enrichment analyses for Gene Ontology, KEGG pathways, PANTHER database, and gene set enrichment analysis (DisGeNET, dbGaP) were performed. Statistical significance was set at a false discovery rate (FDR) of < 0.05. PWH exhibited significant epigenetic age acceleration, with a mean of 19.32 ± 10.82 years greater than chronological age. This accelerated aging was more pronounced in individuals with any prior TB infection (21.60 ± 12.03 years) compared to those without TB (17.42 ± 9.38 years). In the prior active TB vs. no TB comparison, 7461 dmCpGs were identified, corresponding to 150 DMRs (p < 0.05), with top associated genes including GRAMD1C (hypomethylation), DPP6 (hypermethylation), and HDAC4 (hypomethylation). In the LTBI vs. no TB comparison, 8598 dmCpGs were observed, corresponding to 39 DMRs (p < 0.05), associated with genes such as PLEKHG5 (hypermethylation), STK32C (hypermethylation), and SPATC1L. When comparing any prior TB (active or latent) to no TB, 71,774 dmCpGs and 14 DMRs were identified, including genes like PLEKHG5, KCNN3, and BRSK2. Pathway analyses of prior TB (active or latent) vs. no TB revealed enrichment in neurogenesis, neuron differentiation, axon guidance, and neuroactive ligand signaling. Additional enriched pathways included those related to platelet activation, vascular muscle contraction, and chemokine signaling. Cancer-related pathways such as proteoglycans in cancer, small cell lung cancer, prostate cancer, breast cancer, hepatocellular carcinoma, and thyroid cancer were also enriched. PANTHER analysis showed consistent enrichment in the Wnt signaling pathway and inflammation-mediated pathways across compared groups. DisGeNET analysis linked prior TB DNAm patterns to lymphoid leukemia, while dbGaP analysis identified associations with phenotypes like asthma, body mass index, tunica media, and lymphocyte count. Prior TB infection in PWH is associated with distinct DNAm changes in pathways related to neural function, cardiovascular health, and cancer risk, and is linked to more pronounced epigenetic age acceleration, suggesting epigenetic mechanisms for TB-related long-term complications.

Keywords:  Cancer; Cardiovascular disease; DNA methylation; Dementia; HIV; TB

DOI:  https://doi.org/10.1038/s41598-025-15532-5
Cell Commun Signal. 2025 Aug 19. 23(1): 373

Immuno-metabolic diseases and therapeutics: molecular mechanisms via inflammasome signaling.

Joo-Hui Han.

  Inflammatory responses serve as essential defense mechanisms in living organisms, but persistent or excessive activation can contribute to the development of chronic metabolic diseases. A central regulator of such inflammation is the inflammasome, a cytosolic multiprotein complex that senses pathogenic or stress-related signals and triggers the maturation of pro-inflammatory cytokines, particularly interleukin-1β (IL-1β) and interleukin-18 (IL-18). While inflammasome-induced pyroptosis, a form of lytic cell death, can play protective roles in pathogen clearance, excessive or dysregulated activation is more commonly associated with chronic inflammation and tissue damage. Increasing evidence points to the involvement of inflammasomes, especially the NLRP3 inflammasome, in the pathogenesis of immune-metabolic diseases that characterized by the interplay between immune dysfunction and metabolic imbalance, including obesity, diabetes, atherosclerosis, and sarcopenia. In these conditions, aberrant inflammasome activity contributes to insulin resistance, lipid dysregulation, muscle wasting, and vascular injury through sustained cytokine release and immune cell recruitment. Recent studies have advanced our understanding of how inflammasome signaling is integrated into the molecular landscape of metabolic disease, offering new insights into disease mechanisms and highlighting inflammasomes as viable therapeutic targets. This review provides an updated overview of inflammasome biology, defines their role in four representative immune-metabolic diseases, and discusses recent progress in targeting inflammasome pathways as a strategy to mitigate chronic inflammation and metabolic dysfunction.

Keywords:  Atherosclerosis; Diabetes; Inflammasome; Obesity; Sarcopenia

DOI:  https://doi.org/10.1186/s12964-025-02368-9
Mol Biomed. 2025 Aug 20. 6(1): 57

Mucosal immunity and vaccination strategies: current insights and future perspectives.

Zhihao Zhang, Weiqi Hong, Yu Zhang, Xin Li, Haiying Que, Xiawei Wei.

  The mucosal immune system represents a critical defense mechanism, safeguarding the body from an array of external pathogens. As the body's first line of immune protection, it plays an essential role in initiating both innate and adaptive immune responses. Through intricate networks of immune cells and complex molecular pathways, mucosal immunity orchestrates a robust defense not only at the local level but also activates systemic immune responses to ensure comprehensive protection. Consequently, the mucosal immune system has garnered immense interest in the field of vaccine development, given its potential to foster durable and effective immunization. Despite the profound promise of mucosal immunity, the development of mucosal vaccines faces significant challenges, particularly with existing technological platforms that primarily rely on live attenuated or inactivated vaccines. However, emerging innovative platforms, including subunit vaccines, viral vector vaccines, and the groundbreaking application of mRNA vaccines, are offering new perspectives, vastly improving the scope and efficacy of mucosal immunization. As mucosal immunity research continues to evolve, rapid advancements in biotechnology and immunology provide promising strategies to enhance immune responses and overcome inherent limitations. This review delves into the latest progress in oral, nasal, and other forms of mucosal vaccines, analyzing the intricate relationship between mucosal immune characteristics and vaccine design. Emphasis is placed on the pivotal role of advanced adjuvants and delivery systems in maximizing vaccine efficacy. This review addresses current challenges, highlights future research opportunities, and aims to provide a comprehensive framework for advancing the field of mucosal immunity and vaccine development.

Keywords:  Adjuvants; Mucosal immunity; Mucosal technology platform; Vaccine delivery; Vaccine development

DOI:  https://doi.org/10.1186/s43556-025-00301-7