Tuberculosis remains a major risk for people living with HIV, even those on antiretroviral therapy, due to increased susceptibility to latent TB infection. Identifying immune signatures that distinguish progression from resistance is critical for developing predictive biomarkers and targeted prevention strategies. In this study, 80 HIV-infected adults on antiretroviral therapy who received isoniazid preventive therapy (IPT) were followed for six months and categorized as Progressors, Sustainers, Converters, or Resisters based on serial QuantiFERON-TB results. Plasma levels of cytokines, chemokines, and growth factors were analyzed using a Luminex assay, alongside machine learning and pathway analyses. Progressors and Sustainers exhibited elevated proinflammatory cytokines, chemokines, and growth factors, while Resisters showed dynamic immune modulation following preventive therapy. Key predictors of progression included PD-L1, TNF-α, IL-17A, and FGF2. Network and pathway analyses highlighted persistent inflammatory signaling in Progressors and adaptive immune regulation in Resisters. Findings suggest distinct immune profiles associated with TB risk, offering potential for improved prediction and targeted interventions.

Nanomedicine represents one of the pivotal technologies that further bridges critical gaps in precision theranostics through targeted delivery, integrated diagnostics and therapeutics, and personalized treatment. Among various nanocarriers, extracellular vesicles (EVs) have attracted substantial interest owing to their nanoscale dimensions, favorable biocompatibility relative to synthetic counterparts, and innate capacity to transport bioactive cargoes. The central focus in this field is the inherent heterogeneity of EVs, which provides promising opportunities for biomarker-driven patient stratification while presents significant challenges in quality control and batch reproducibility. Recent progress in surface engineering has significantly optimized the targeting capability and pharmacokinetic profiles of EV-based systems in preclinical models, yet their clinical translation remains restricted by major challenges, including manufacturing scalability and the lack of disease and subgroup-specific standardization. Given that EV functionality and safety are highly context-dependent varying with cell source, loading strategy, and recipient pathophysiology bridging the gap between large-scale production and patient-specific customization emerges as a critical priority for translating EV-based nanomedicines into routine precision oncology treatment and beyond.

The nuclear receptor NOR-1 is a key transcription factor in vascular smooth muscle cells (VSMCs) implicated in the pathogenesis abdominal aortic aneurysm (AAA), a life-threatening disease lacking pharmacological options. Here, we aimed at identifying potential therapeutic targets regulated by NOR-1 in the onset and progression of AAA. RNA-seq analysis in dilated arteries from AngII-infused transgenic mice overexpressing NOR-1 in VSMCs (TgNOR-1[VSMC]) revealed an early transcriptomic signature enriched in immune-inflammatory and tissue remodeling pathways. Biologically informed analysis identified a set of genes (Spp1, Il6, Tnfsf11, Grem1, Fcgr4, Adam8 and Mmp9), linking immune-inflammatory and vascular remodeling pathways, upregulated in TgNOR-1[VSMC] dilated aortas. Re-analysis of RNA-seq datasets from human AAA aortas revealed the activation of inflammation- and extracellular matrix (ECM)-related pathways, with SPP1 and IL6 as the most upregulated genes in both clusters. In human AAA, NOR-1 expression correlated with that of SPP1 and IL6, while luciferase reporter assays and site-directed mutagenesis indicated that NOR-1 increases SPP1 transcriptional activity. Consistently, gain- and loss-of-function studies showed that NOR-1 regulates SPP1 expression. Integrative co-expression and protein-protein interaction analysis in human AAA identified SPP1 as a critical element at the cross-road between ECM remodelling and vascular inflammation. Inhibition of osteopontin (OPN, encoded by Spp1) with HY-146064 attenuated AngII-induced AAA in TgNOR-1[VSMC] mice, limiting vascular remodelling, oxidative stress, and inflammation. Overall, we identify NOR-1 as an early driver of transcriptional reprogramming in AAA, establishing the NOR-1/SPP1/OPN axis as a key mediator of the cross-talk between inflammation and vascular remodelling, and a potential therapeutic target for disease intervention.

Histone post-translational modifications play a major role in gametogenesis and early embryogenesis, being closely associated with in vitro fertilization (IVF). Proper regulation of histone modifications enables chromatin compaction, transcriptional activity, parental imprint establishment and genomic reprogramming which are essential events for zygotic genome activation and lineage specification post-fertilization. Aberrant histone regulation can disrupt epigenetic integrity, leading to impaired gamete quality, defective embryonic development, imprinting errors and potential long-term offspring implications. This review provides a critical overview of the recent findings linking assisted reproduction procedures to altered histone profiles and adverse embryonic outcomes. Emerging epigenetic strategies, including epigenetic monitoring, epigenetic editing tools (CRISPR-dCas9), optimal epigenetic quality control in IVF labs and multi-omics approaches are thoroughly discussed, aiming to optimize IVF and enhance embryo health.

Endothelial dysfunction underpins the pathogenesis of sepsis-induced acute lung injury (SI-ALI), wherein neutrophil extracellular traps (NETs) serve as pivotal mediators driving excessive inflammatory responses and progressive tissue deterioration. This study aimed to elucidate the molecular mechanism by which NETs disrupt endothelial homeostasis and promote vascular dysfunction during sepsis. In vivo mice models and in vitro endothelial cell experiments consistently demonstrated that NETs markedly exacerbated endothelial barrier disruption and autophagic flux impairment. Mechanistically, NETs-derived S100A8/A9 activated the PI3K-AKT-mTOR signaling pathway via toll-like receptor 4 (TLR4), thereby triggering endothelial pro-inflammatory and pro-adhesive phenotypic transformation. S100A8/A9 also promoted reactive oxygen species (ROS) production and NET formation in neutrophils, forming a vicious cycle. Pharmacological inhibition of S100A8/A9 or TLR4 effectively restored autophagy and mitigated sepsis-associated lung injury. Collectively, these findings reveal that the S100A8/A9-TLR4-PI3K-AKT-mTOR-autophagy axis critically mediates NETs-induced endothelial dysfunction, providing promising therapeutic targets for the intervention of septic acute lung injury.

This study is the first to investigate whether modulation of the lung microbiome after traumatic brain injury (TBI) can reduce secondary brain injury and promote neurological recovery. Moderate TBI was induced in adult male Sprague-Dawley rats, which were assigned to normal, TBI, or TBI with intratracheal neomycin treatment for three days. Bronchoalveolar lavage fluid (BAL) and lung tissues were collected on day 3, and brain neuropathology, neuroinflammation, and cognition were assessed on day 7. TBI induced marked neutrophil infiltration and alveolar interstitial edema, accompanied by elevated IL-6 and NOS2 expression in BAL fluid and increased Acinetobacter abundance (LEfSe, LDA score > 3, p < 0.05). Intratracheal neomycin treatment after TBI corrected lung dysbiosis, significantly reduced Acinetobacter abundance, and suppressed IL-6, RAGE, and NLRP3 inflammasome components (NLRP3, ASC, caspase-1, and IL-1β) in lung tissues. In the brain, neomycin improved novel object recognition, reduced IL-6, IL-1β, and NLRP3 inflammasome activation, attenuated GFAP and Iba-1 activation, decreased FJB- and TUNEL-positive cells, preserved blood-brain barrier integrity, and prevented synaptic injury. Serum IL-1β levels peaked on day 3 after TBI, but this elevation was substantially attenuated in neomycin-treated rats. Furthermore, restoration of viable Acinetobacter baumannii largely reversed the neuroprotective effects of neomycin, supporting a causal role for lung Acinetobacter in secondary brain injury after TBI. These findings suggest that early intratracheal neomycin instillation following TBI mitigates lung dysbiosis and NLRP3-mediated inflammation in both lung and brain, thereby reducing secondary brain injury via the lung-brain axis, highlighting translational therapeutic potential.

Interleukin-1 (IL-1) signaling is a key mediator of metabolic inflammation, yet its tissue-specific contribution to obesity-associated dysfunction remains incompletely understood. Here, we investigated the effects of pharmacological IL-1 receptor antagonism on systemic metabolism, adipose tissue dysfunction, and hepatic lipid handling under distinct nutritional conditions. Male mice fed a normal diet (ND) or high-fat diet (HFD) were treated subcutaneously with the IL-1 receptor antagonist (IL-1RA) anakinra for three weeks. IL-1RA did not significantly affect body weight or global adiposity; however, under ND conditions, it reduced fat mass and circulating leptin levels and increased the adiponectin/leptin ratio, indicating improved adipose endocrine function. In adipose tissue, IL-1RA partially restored Acaca expression and selectively modulated extracellular matrix remodeling genes, including Mmp9, without broadly suppressing inflammatory markers. In the liver, triglyceride content was altered in a diet-dependent manner without changes in the expression of key metabolic genes (Fasn, Acaca, Ppara), suggesting that IL-1 blockade does not directly reprogram intrinsic hepatic lipid metabolism. Consistent with this, analyses in complementary models, including leptin-deficient mice, showed that Il1rn expression is regulated by local inflammatory and endocrine cues rather than adiposity per se. Together, these findings identify IL-1 signaling as a context-dependent modulator of adipose tissue function and systemic lipid handling. The dissociation between adipose tissue responses and hepatic triglyceride accumulation highlights the tissue-specific effects of IL-1 receptor antagonism and underscores the need for direct metabolic flux studies to define the mechanisms underlying these effects.

MGAT5-mediated N-glycosylation plays a central role in tumor progression and metastasis by affecting proteins involved in tumor cell behavior. One relevant target is Tissue inhibitor of metalloproteases 1 (TIMP1), which, beyond its classical role as a metalloproteinase inhibitor, promotes oncogenic signaling through interactions with CD63 and β1-integrins. Emerging evidence suggests that aberrant TIMP1 N-glycosylation may regulate these diverse functions. Here, we investigated the role of MGAT5 in melanoma cell behavior and how MGAT5-mediated aberrant N-glycosylation influences TIMP1 function, including its activity as a signaling molecule and as an inhibitor of metalloproteinases. We performed Mgat5 knockout using CRISPR/Cas9 in metastatic melanoma cells to understand the role of MGAT5 in cell proliferation, migration, invasion, and tumor growth. Through site-directed mutagenesis, we generated melanoma cells expressing aglycosylated TIMP1 and evaluated the effect of N-glycosylation on TIMP1 function, including its role as a signaling molecule, by co-immunoprecipitation and anoikis resistance assays, and as an inhibitor of metalloproteinases, by zymography. We demonstrated that Mgat5 knockout reduced metastatic melanoma cell proliferation, migration, invasion, and tumor growth, TIMP1 is a target of MGAT5 in metastatic melanoma cells, and aberrant glycosylation of TIMP1 favors its interaction with CD63/β1-integrins and cell survival while decreasing its ability to inhibit metalloproteases (MMPs). Therefore, MGAT5 plays a pro-tumor role in metastatic melanoma cells and the aberrant glycoform of TIMP1 directs its function as a signaling molecule, orchestrating the pleiotropic functions of TIMP1.

Triple-negative breast cancer (TNBC) poses a significant clinical challenge due to its aggressive nature and lack of targeted therapies. A subset expressing the Androgen Receptor (AR) offers a therapeutic opportunity, yet the mechanisms remain incompletely understood. Breast cells were cultured under hormone-deprived or androgen-stimulated conditions with or without AR inhibitors. Short hairpin RNA knockdown or overexpression of AR, ARD1, and DLGAP5 was performed. Functional assays included CCK-8, colony formation, migration and invasion, and apoptosis by flow cytometry. Protein interactions and transcriptional regulation were examined using co-immunoprecipitation and chromatin immunoprecipitation. In vivo, xenograft models of TNBC were established in BALB/c nude mice. Clinical relevance was validated using paired TNBC and adjacent normal tissues. AR and ARD1 were co-upregulated in AR+ TNBC cells and tissues, correlating with poor prognosis. ARD1 promoted TNBC malignant phenotypes in vitro and in vivo. Mechanistically, androgens induced ARD1 protein stabilization via AR. ARD1 physically interacted with AR, enhanced AR acetylation, and potentiated AR transcriptional activity. DLGAP5 was identified as a transcriptional target co-regulated by AR and ARD1. DLGAP5 upregulation promoted tumor growth and drove expression of the immune checkpoint ligand PD-L1 via signal transducer and activator of transcription 3, suppressing cytotoxic T-cell marker expression. In vivo, DLGAP5 overexpression accelerated tumor growth and increased PD-L1; treatment with an AR PROTAC reversed these effects. ARD1 acts as a critical AR coactivator, driving DLGAP5 expression, which subsequently promotes tumor progression and immune evasion through PD-L1 upregulation. Targeting the AR/ARD1/DLGAP5 axis represents a promising therapeutic strategy for this breast cancer subtype.

Gemcitabine resistance remains a major barrier to effective therapy in pancreatic ductal adenocarcinoma (PDAC), and current combination regimens show potential to overcome this resistance. Here, we identify the mitochondrial ribosomal proteins MRPS22 and MRPL3 as key metabolic gatekeepers that maintain mitochondrial OXPHOS and pyrimidine metabolism, thereby promoting pancreatic cancer cell proliferation and chemoresistance. Across independent cohorts, high MRPS22/MRPL3 expression associates with poorer survival. Depletion of either gene in PDAC curtailed cell proliferation and xenograft growth, which might be due to an impaired mitochondria function, including destabilized respiratory super-complex assembly, diminished ATP production, and increased oxidative stress. Multi-omics profiling revealed a broad reduction of central-carbon intermediates and a pronounced blockade of de novo pyrimidine synthesis at the dihydroorotate dehydrogenase (DHODH) node. MRPS22 depletion hampered nucleotide-pool generation, and exogenous deoxynucleotides partially rescued PDAC cell growth when MRPs were knocked down. Pharmacologic OXPHOS inhibition increased gemcitabine sensitivity, whereas gemcitabine-resistant derivatives exhibited heightened OXPHOS activity and upregulated mitochondrial ribosomal programs. Co-targeting OXPHOS (antimycin A) or DHODH (brequinar) with gemcitabine produced Loewe synergy in vitro and suppressed growth of gemcitabine-resistant xenografts without affecting body weight. Collectively, these findings established MRPS22/MRPL3 as translation-level drivers of PDAC metabolic fitness and nominate OXPHOS/DHODH blockade as a rational combination strategy to overcome gemcitabine resistance.