Patients with liver cirrhosis may develop minimal hepatic encephalopathy (MHE) with mild cognitive impairment. Hyperammonemia is a main contributor to cognitive impairment in MHE, which is mediated by neuroinflammation. GABAergic neurotransmission is altered in hyperammonemic rats. We hypothesized that, in hyperammonemic rats, (a) enhanced GABAergic tone would contribute to induce neuroinflammation, which would be improved by reducing GABAergic tone by chronic bicuculline treatment; (b) this would improve spatial learning and memory impairment; and (c) modulation of glutamatergic neurotransmission would mediate this cognitive improvement. The aim of this work was to assess the above hypotheses. Bicuculline was administrated intraperitoneally once a day for 4 weeks to control and hyperammonemic rats. The effects of bicuculline on microglia and astrocyte activation, IL-1β content, on membrane expression of AMPA and NMDA glutamate receptors subunits in the hippocampus and on spatial learning and memory as well as anxiety were assessed. Treatment with bicuculline reduces astrocyte activation and IL-1β but not microglia activation in the hippocampus of hyperammonemic rats. Bicuculline reverses the changes in membrane expression of AMPA receptor subunits GluA1 and GluA2 and of the NR2B (but not NR1 and NR2A) subunit of NMDA receptors. Bicuculline improves spatial learning and working memory and decreases anxiety in hyperammonemic rats. In hyperammonemia, enhanced activation of GABA_A receptors in the hippocampus contributes to some but not all aspects of neuroinflammation, to altered glutamatergic neurotransmission and to impairment of spatial learning and memory as well as anxiety, all of which are reversed by reducing activation of GABA_A receptors with bicuculline.

In general, the risk of being diagnosed with cancer increases with age; however, the development of estrogen-receptor-positive (ER+) cancer types in women are more closely related to menopausal status than age. In fact, the general risk factors for cancer development, such as obesity-induced inflammation, show differences in their association with ER+ cancer risk in pre- and postmenopausal women. Here, we tested the role of the principal estrogens in the bloodstream before and after menopause, estradiol (E2) and estrone (E1), respectively, on inflammation, epithelial-to-mesenchymal transition (EMT) and cancer stem cell enrichment in the human ER+ cervical cancer cell line HeLa. Our results demonstrate that E1, contrary to E2, is pro-inflammatory, increases embryonic stem-transcription factors (ES-TFs) expression and induces EMT in ER+ HeLa cells. Moreover, we observed that high intratumoural expression levels of 17β-Hydroxysteroid dehydrogenase (HSD17B) isoforms involved in E1 synthesis is a poor prognosis factor, while overexpression of E2-synthetizing HSD17B isoforms is associated with a better outcome, for patients diagnosed with ER+ ovarian and uterine corpus carcinomas. This work demonstrates that E1 and E2 have different biological functions in ER+ gynaecologic cancers. These results open a new line of research in the study of ER+ cancer subtypes, highlighting the potential key oncogenic role of E1 and HSD17B E1-synthesizing enzymes in the development and progression of these diseases.

Cardiovascular disease (CVD) is the biggest cause of sickness and mortality worldwide in both males and females. Clinical statistics demonstrate clear sex differences in risk, prevalence, mortality rates, and response to treatment for different entities of CVD. The reason for this remains poorly understood. Non-coding RNAs (ncRNAs) are emerging as key mediators and biomarkers of CVD. Similarly, current knowledge on differential regulation, expression, and pathology-associated function of ncRNAs between sexes is minimal. Here, we provide a state-of-the-art overview of what is known on sex differences in ncRNA research in CVD as well as discussing the contributing biological factors to this sex dimorphism including genetic and epigenetic factors and sex hormone regulation of transcription. We then focus on the experimental models of CVD and their use in translational ncRNA research in the cardiovascular field. In particular, we want to highlight the importance of considering sex of the cellular and pre-clinical models in clinical studies in ncRNA research and to carefully consider the appropriate experimental models most applicable to human patient populations. Moreover, we aim to identify sex-specific targets for treatment and diagnosis for the biggest socioeconomic health problem globally.

Triple-negative breast cancer (TNBC) remains a challenging subtype of breast cancer due to its aggressive nature and lack of targeted therapies. Cytokines play a pivotal role in shaping the tumor microenvironment, modulating tumor progression, immune evasion, and therapy resistance. In this review, we discuss the complex cytokine networks involved in TNBC biology, highlighting their contribution to key oncogenic processes, including proliferation, angiogenesis, epithelial–mesenchymal transition, and immunomodulation. We also summarize current and emerging cytokine-targeted therapeutic strategies, including monoclonal antibodies, bispecific antibodies, cell-based therapies, and cytokine-armed CAR-T and CAR-NK cell approaches, with a focus on clinical implications and future directions.

Background: Glioblastoma (GBM) is a highly heterogeneous and vascularized malignancy in which the mesenchymal (MES) subtype is associated with poor prognosis, extensive macrophage infiltration and resistance to therapy. However, the signaling mechanisms integrating vascular remodeling with inflammatory tumor-macrophage crosstalk remain incompletely understood. Methods: We integrated magnetic resonance imaging-derived vascular phenotyping with transcriptomic analyses of human glioblastoma cohorts to identify molecular pathways associated with highly vascular tumors. Functional studies using glioblastoma cell lines, THP-1-derived macrophages and co-culture systems were performed to investigate the role of PI3K signaling in tumor-macrophage communication. Finally, an independent single-cell transcriptomic cohort of primary human glioblastoma was interrogated to determine whether the identified inflammatory programs were conserved in malignant cells from patient tumors. Results: Integrated imaging-transcriptomic analyses identified highly vascular glioblastomas as tumors enriched for the MES subtype, increased macrophage infiltration and activation of PI3K-associated signaling. Pharmacological inhibition of PI3K reduced the expression of macrophage-recruiting cytokines and impaired the ability of glioblastoma cells to educate macrophages toward an immunosuppressive phenotype. Reciprocally, tumor-educated macrophages enhanced inflammatory signaling, immune checkpoint expression and migratory capacity in glioblastoma cells, whereas IL-6 blockade attenuated these effects, identifying IL-6 as a key mediator of this bidirectional communication. To determine whether these inflammatory programs were conserved in human disease, we analyzed an independent single-cell transcriptomic dataset of primary glioblastomas. MES-like malignant cells exhibited the strongest inflammatory transcriptional programs among the four malignant transcriptional states, including higher NF-κB activation program scores and tumor-macrophage communication signature scores. At the tumor level, MES-like enrichment was positively associated with higher inflammatory program activity, supporting the clinical relevance of the proposed signaling axis. Conclusions: Together, our findings identify PI3K signaling as a central regulator integrating vascular remodeling with inflammatory tumor-macrophage communication in mesenchymal glioblastoma. These results provide a mechanistic framework linking PI3K signaling, macrophage education and the MES phenotype, and provide a rationale for therapeutic strategies aimed at disrupting inflammatory signaling within the glioblastoma microenvironment.

Triple-negative breast cancer (TNBC) is characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and HER2 expression on tumor cells. Compared to other breast cancer subty...