Search Results (422)

Background/Objectives: Trophoblast cell surface antigen 2 (Trop2), a transmembrane glycoprotein overexpressed in a broad spectrum of epithelial malignancies but minimally expressed in normal tissues, has emerged as a clinically relevant prognostic biomarker and therapeutic target, particularly in breast cancer. This study aims to develop an enhanced way of targeting Trop2 expression in tumors and blocking it using extracellular vesicles (EVs) bioengineered to express a nanobody sequence against Trop2 (NB60 E). Methods: Here, a plasmid construct was designed to express the Trop2 sequence, NB60, flanked with HA tag and myc epitope and a PDGFR transmembrane domain in the C-terminal region, and was transfected into HEK293T cells for EVs isolation. The potency of NB60 E to knock down Trop2 in letrozole-resistant breast cancer cells (LTLT-Ca and MDA-MB-468 cells) was initially investigated. Thereafter, the effects of NB60 E on the cell viability and downstream signaling pathway of Trop2 via MTT assay and Western blotting were determined. Lastly, we also examined whether NB60 E treatment in Jurkat T cells affects IL-6, TNF-α, and IL-2 cytokine production by enzyme-linked immunosorbent assay (ELISA). Results: Results revealed treatment with NB60 E significantly reduced surface Trop2 expression across both cell lines by 23.5 ± 1.5% in MDA-MB-468, and 61.5 ± 1.5% in LTLT-Ca, relative to the HEK293T-derived control EVs (HEK293T E). NB60 E treatment resulted in a marked reduction in LTLT-Ca cell viability by 52.8 ± 0.9% at 48 h post-treatment. This was accompanied by downregulation of key oncogenic signaling molecules: phosphorylated ERK1/2 (p-ERK 1/2) decreased by 30 ± 4%, cyclin D1 by 67 ± 11%, phosphorylated STAT3 (p-STAT3) by 71.8 ± 1.6%, and vimentin by 40.8 ± 1.4%. ELISA analysis revealed significant decreases in IL-6 (−57.5 ± 1.5%, 7.4 ± 0.35 pg/mL) and TNF-α (−32.1 ± 0.3%, 6.1 ± 1.2 pg/mL) levels, coordinated by an increase in IL-2 secretion (22.1 ± 2.7%, 49.2 ± 1.1 pg/mL). Quantitative analysis showed marked reductions in the number of nodes (−45 ± 4.4%), junctions (−55 ± 3.5%), and branch points (−38 ± 1.2%), indicating suppression of angiogenic capacity. In vivo experiment using near-infrared Cy7 imaging demonstrated rapid and tumor-selective accumulation of NB60 E within 4 h post-administration, followed by efficient systemic clearance by 24 h. The in vivo results demonstrate the effectiveness of NB60 E in targeting Trop2-enriched tumors while being efficiently cleared from the system, thus minimizing off-target interactions with normal cells. Lastly, Trop2 expression in LTLT-Ca tumor xenografts revealed a significant reduction of 41.0 ± 4% following NB60 E treatment, confirming efficient targeted delivery. Conclusions: We present a first-in-field NB60 E-grafted EV therapy that precisely homes to Trop2-enriched breast cancers, silences multiple growth-and-invasion pathways, blocks angiogenesis, and rewires cytokine crosstalk, achieving potent antitumor effects with self-clearing, biomimetic carriers. Our results here show promising potential for the use of NB60 E as anti-cancer agents, not only for letrozole-resistant breast cancer but also for other Trop2-expressing cancers. Full article

Pseudorabies virus (PRV), a major swine pathogen, causes severe neurological, respiratory, and reproductive disorders, resulting in substantial economic losses to the global swine industry. Previous studies have shown that the gD glycoprotein of PRV has an effective protective effect. In this study, we constructed a plasmid DNA vaccine (pVAX1-GD-Fc) encoding a gD protein fused with pig IgG Fc and evaluated the adjuvant effects of porcine cGAS, the universal STING complex mimic (UniSTING), or IFN-α in mice. The mice were immunized three times (days 0, 14, and 21) with pVAX1-GD-Fc in the presence or absence of an adjuvant, followed by lethal challenge with PRV-HLJ8 3 days after the final immunization. The results revealed that the pVAX1-GD-Fc group exhibited 20% mortality (1/5 mice) on day 7 postchallenge, and all adjuvanted groups achieved 100% survival during the 14-day observation period. Flow cytometric analysis of splenocytes one week after the second immunization revealed significantly greater CD8+ T cell proportions in the adjuvant groups than in both the mock and pVAX1-GD-Fc-only control groups (p < 0.01). Furthermore, T cell proliferation assays demonstrated a significantly increased stimulation index in the adjuvant-treated mice, confirming enhanced cellular immunity. These findings demonstrate that cGAS, UniSTING, and IFN-α can serve as effective vaccine adjuvants to rapidly enhance cellular immune responses to PRV, highlighting their potential application in veterinary vaccines. Full article

Cadherin 17 (CDH17) is a cell adhesion glycoprotein essential for epithelial integrity. It is frequently overexpressed in various cancers, where it is associated with aggressive behaviour. While evidence indicates that CDH17 functions as an upstream regulator of Wnt/β-catenin signalling, findings are inconsistent across tumour types, limiting the assessment of CDH17 as a biomarker or therapeutic target for Wnt pathway in cancer. In this study, we systematically review and meta-analyse the relationship between CDH17 and Wnt/β-catenin signalling in human cancers and evaluate whether CDH17 modulation affects tumour behaviour through Wnt-related mechanisms. Our search of Medline, Web of Science and Scopus identified five studies examining CDH17 expression in the Wnt/β-catenin pathway in vitro and in vivo. All five studies identified CDH17 as a key driver of canonical Wnt signalling, directly influencing cancer progression in hepatocellular carcinoma (HCC), gastric cancer (GC), and colorectal cancer (CRC). Meta-analysis (MA) showed that CDH17 inhibition consistently reduced Wnt/β-catenin downstream T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) transcriptional activity (MD = −1.32, 95% CI: −1.64 to −0.99, p < 0.00001). Narrative synthesis found that CDH17 suppression decreased total and nuclear β-catenin, phosphorylated glycogen synthase kinase-3 beta (GSK-3β), and cyclin D1 while increasing tumour suppressors, retinoblastoma (Rb) and p53/p21. These changes were associated with reduced proliferation, colony formation, migration, invasion and cell cycle arrest. In vivo, CDH17 suppression resulted in 80–95% tumour growth suppression (Mean Difference (MD) = −96.67, 95% CI: [−144.35, −48.98], p < 0.0001), with immunohistochemistry confirming cytoplasmic β-catenin sequestration and lower cyclin D1 levels. Collectively, these findings show CDH17 as a critical upstream effector sustaining Wnt/β-catenin signalling, cancer progression, tumour proliferation, stem cell properties, and metastasis, and support CDH17 inhibition as a promising therapeutic target across multiple cancer types. Full article

Virus-associated hepatocellular carcinoma (HCC) remains a major global health burden despite effective antiviral therapies. Chronic infection with hepatitis B (HBV), hepatitis C (HCV), and hepatitis D (HDV) promotes malignant transformation through overlapping pathways of fibrosis, immune dysregulation, and microenvironmental remodeling. YKL-40, a glycoprotein secreted by hepatic stellate cells, hepatocytes under stress, macrophages, and endothelial cells, has emerged as a marker that reflects stromal activation rather than direct hepatocyte injury. Its expression is reinforced by profibrotic and angiogenic circuits, and circulating concentrations correlate with advanced fibrosis, residual risk after viral suppression, and oncologic outcomes. This review synthesizes current evidence on YKL-40 across HBV, HCV, and HDV cohorts, with emphasis on its role in bridging molecular mechanisms to clinical applications. We examine its utility in non-invasive fibrosis assessment, longitudinal monitoring after antiviral therapy, and prognostic modeling in HCC. Particular attention is given to its potential in the liver transplant pathway, where YKL-40 may refine eligibility beyond morphology, inform bridging therapy response, and predict post-transplant recurrence or graft fibrosis. Remaining challenges include its lack of disease specificity, assay variability, and limited multicenter validation. Future integration of YKL-40 into multimarker, algorithm-based frameworks could enable risk-adaptive strategies that align surveillance and transplant decisions with the evolving biology of virus-associated liver disease. Full article

Authorized SARS-CoV-2 vaccines elicit both antibody and T-cell responses; however, benchmark correlates and update decisions have largely emphasized neutralizing antibodies. Motivated by the complementary role of cellular immunity, we designed a prototype polyepitope DNA vaccine encoding conserved human and mouse T-cell epitopes from non-structural proteins of the original strain SARS-CoV-2 lineage. Epitope selection was guided by in silico predictions for common HLA class I alleles in the Brazilian population and the mouse H-2Kb haplotype. To enhance immunogenicity, the polyepitope sequences were fused to glycoprotein D (gD) from Herpes Simplex Virus 1 (HSV-1), an immune activator of dendritic cells (DCs), leading to enhanced activation of antigen-specific T-cell responses. Mice were immunized with two doses of the electroporated DNA vaccine encoding the gD-fused polyepitope, which induced robust interferon-gamma– and tumor necrosis factor-alpha–producing T cell responses compared to control mice. In addition, K18-hACE2 transgenic mice showed protection against intranasal challenge with the original SARS-CoV-2 strain, with reduced clinical symptoms, less weight loss, and decreased viral burden in both lung and brain tissues. The results experimentally confirm the protective role of T cells in vaccine-induced protection against SARS-CoV-2 and open perspectives for the development of universal anti-coronavirus vaccines. Full article

Leptin, an adipocyte-derived hormone, plays a central role in the regulation of energy homeostasis by acting on distinct hypothalamic nuclei. This review explores recent advances in our understanding of leptin’s region-specific actions within the arcuate nucleus, ventromedial hypothalamus, dorsomedial hypothalamus, and lateral hypothalamus, highlighting their contributions to appetite regulation, energy expenditure, and neuroendocrine function. In the hypothalamic arcuate nucleus, leptin’s differential regulation of pro-opiomelanocortin and agouti-related peptide/neuropeptide Y neurons is now complemented by the identification of novel leptin-responsive neuronal populations—such as those expressing prepronociceptin, basonuclin 2, and Pirt—as well as a growing array of cellular and molecular modulators, including secreted factors like angiopoietin-like growth factor, zinc-α2-glycoprotein, and spexin, intracellular regulators such as Rap1, growth factor receptor-bound protein 10, and spliced X-box binding protein 1. In the ventromedial hypothalamus, leptin integrates with both peripheral (e.g., cholecystokinin) and central (e.g., pituitary adenylate cyclase-activating polypeptide) signals, while epigenetic mechanisms, such as those mediated by Jumonji domain-containing protein D3, regulate leptin receptor expression and sensitivity. The dorsomedial hypothalamus is increasingly recognized for coordinating leptin’s effects on metabolism, circadian rhythms, and respiration through distinct neuronal populations, including a subset of neurons co-expressing GLP-1 receptors that mediate leptin’s metabolic effects. In the lateral hypothalamus, leptin modulates reward-driven feeding via GABAergic neuronal populations—circuits that are particularly susceptible to disruption following early life trauma. Together, these insights reveal a sophisticated neurobiological framework through which leptin orchestrates systemic physiology. Understanding the heterogeneity of leptin signaling opens new avenues for restoring leptin sensitivity and developing personalized therapeutic strategies to combat obesity and related metabolic disorders. Full article

Plexiform neurofibromas (hereafter called pNF1) are often diagnosed in early childhood and occur in about 30% of neurofibromatosis type 1 (NF1) patients. pNF1 exhibits aggressive growth along a nerve in the body and has substantial potential for progression to malignant peripheral nerve sheath tumors that are rarely curable. There are two recently FDA-approved drugs, selumetinib and mirdametinib, for pNF1 patients who have symptomatic and inoperable plexiform neurofibromas; however, these treatments achieve only approximately 30% tumor shrinkage. Fibroblasts, the most abundant cell types within the pNF1 tumor microenvironment, are implicated in pNF1 growth and invasion; however, how fibroblasts affect a drug response of pNF1 remains poorly understood. In the present study, we focused on contributions of fibroblasts to the drug resistance in pNF1 via their secretome. We employed our established three-dimensional (3D) culture system incorporating human pNF1 tumor cells (Nf1^−/−) and primary fibroblasts (Nf1^+/−) grown in our patented microfluidic culture chips for monocultures and parallel cocultures in which 3D pNF1 structures and fibroblasts share their secretome without direct cell-to-cell contact. Three-dimensional pNF1 structures in 3D parallel cocultures with fibroblasts exhibited greater drug resistance than ones in monocultures. We found that pNF1 tumor cells showed increased P-glycoprotein expression when incubated with fibroblast-derived conditioned media or parallel cocultured with fibroblasts, compared to control conditions. Pharmacological inhibition of P-glycoprotein partially restored drug sensitivity. Additionally, fibroblasts showed higher resistance to selumetinib and mirdametinib than pNF1 tumor structures, likely due to elevated P-glycoprotein levels. This study is the first to define precise roles of fibroblasts in pNF1 drug resistance, emphasizing the potential of fibroblast-targeted therapies as a promising approach to improve pNF1 treatment outcomes. Full article

The molecular basis for the distinct intestinal tropism of infectious bronchitis virus (IBV) strains remains poorly understood. This study identifies the S2 subunit of the spike glycoprotein as the critical determinant conferring duodenal tropism to the IBV CSL strain. Comparative pathogenesis in specific-pathogen-free (SPF) chicks revealed that the CSL strain achieved significantly higher viral titers in the duodenum compared to strains D90, PYG QX1, and XXX QX5. This duodenal replication was associated with severe epithelial inflammation, characterized by upregulation of pro-inflammatory cytokines (IL-6, IL-17A, IL-22, TNF-α, IFN-β, IFN-γ) and disruption of barrier integrity via downregulation of tight junction proteins (Occludin, Claudin-1, ZO-1). Crucially, reverse genetics using the non-enterotropic D90 backbone demonstrated that recombinant viruses carrying the CSL-S2 gene (rD90-ΔS/CSL and rD90-ΔS2/CSL), but not those carrying CSL-S1 (rD90-ΔS1/CSL), replicated efficiently and induced inflammation in the duodenum, phenocopying wild-type CSL. In contrast, renal tropism was independent of the S2 subunit. These findings establish the S2 subunit as both necessary and sufficient for IBV duodenal tropism, uncoupling it from renal pathogenicity. This identifies S2 as a prime molecular target for developing next-generation vaccines against intestinal IBV pathotypes. Full article

Hemopexin (HPX) is a heme-binding glycoprotein involved in detoxification, oxidative stress regulation, and immune defense. In teleosts, gene duplication gave rise to Wap65-1 and Wap65-2, but the structure and function of ancestral HPX in basal actinopterygians remain poorly understood. Here, we characterized HPX from the Siberian sturgeon (Acipenser baerii), a slow-evolving chondrostean species that diverged prior to the teleost-specific duplication. Structural modeling and superimposed 3D alignment revealed high similarity between sturgeon HPX, human HPX, and Wap65-2, but not Wap65-1. Phylogenetic analysis placed sturgeon HPX in a distinct basal clade within the Actinopterygian lineage, positioned below the divergence of Wap65 paralogs. Tissue expression was liver-dominant but also evident in skin and kidney, and HPX transcripts increased during larval development. Under Aeromonas hydrophila challenge, HPX was strongly upregulated in immune-relevant tissues. Thermal challenge also induced modest, tissue-specific changes, particularly in peripheral tissues. These results indicate that ancestral HPX possessed multivalent stress responsiveness—primarily immune-related—with supplementary thermal sensitivity. The observed functional flexibility is consistent with the hypothesis that ancestral HPX functions were partitioned following Wap65 gene duplication in teleosts, with Wap65-1 evolving toward a specialized thermal response role. Full article

P-glycoprotein (Pgp) plays a significant role in the disposition of cardiac glycoside (CG) drugs across the cell membrane. The relatively narrow therapeutic indices of these drugs, coupled with the co-administration of drugs that inhibit Pgp’s transport mechanism, often cause an increased level of CG in the patient’s plasma, resulting in fatal arrhythmia. Therefore, understanding the underlying mechanism of the CG–Pgp interaction is necessary to circumvent Pgp-mediated transport and effectively design next-generation CGs. In this study, we conducted a comparative analysis to examine the interaction with Pgp and further understand the Pgp-mediated transport of digoxin, digitoxin, digoxigenin, and digitoxigenin. Through the drug-induced kinetic studies of Pgp, our findings suggest that each of the four drugs tested has a single binding site within Pgp. The CG–Pgp binding studies demonstrated that digoxin, digitoxin, and digoxigenin had relatively higher binding affinities. The CG-mediated conformational changes in Pgp indicated that each of the drugs shifts Pgp to an “outward-open” conformation in a nucleotide-dependent manner. STDD NMR indicated that the protons within the δ-lactone ring and the tri-D-digitoxose sugar moieties (glycones) predominantly interact with Pgp. Finally, a model was proposed for CG-induced Pgp-mediated ATP hydrolysis and transport by integrating our data with previously published Pgp-mediated CG transport results. Full article

Skin aging is commonly characterized by increased wrinkles, loss of elasticity, and hyperpigmentation, significantly affecting personal appearance and quality of life. Although botulinum toxin type A (BTX-A) has been widely applied in cosmetic anti-wrinkle treatments, its intrinsic cytotoxicity limits broader clinical applications. In this study, we developed a novel exosome-based BTX-A composite delivery system designed to synergize the anti-aging properties of exosomes with the wrinkle-reducing effects of BTX-A while reducing toxicity. Human adipose-derived mesenchymal stem cells were genetically modified via lentiviral transduction to overexpress Synaptic Vesicle Glycoprotein 2C (SV2C), the receptor of BTX-A, thereby producing SV2C-enriched functionalized exosomes (EXO^SV2C). These exosomes (2.0 × 10⁷ particles/mL) were incubated with BTX-A (3 U/mL) to generate the EXO^SV2C-BTX-A complex. In vitro, EXO^SV2C-BTX-A significantly promoted the proliferation and migration of human dermal fibroblasts and effectively alleviated D-galactose (D-gal)-induced cellular senescence and collagen type I loss. These effects were superior to those observed with either BTX-A or exosomes alone. In vivo, intradermal injection of EXO^SV2C-BTX-A for 28 days markedly suppressed D-gal-induced skin aging in 8-week-old male KM mice, as evidenced by reduced malondialdehyde levels in dermal tissue, enhanced collagen type I expression, and preserved skin structure. Notably, the composite exhibited significantly lower toxicity compared to free BTX-A. Collectively, these findings highlight EXO^SV2C-BTX-A as a promising exosome-mediated BTX-A delivery platform with enhanced anti-aging efficacy and improved biocompatibility, offering a potential therapeutic strategy for skin rejuvenation. Full article

Bubaline alphaherpesvirus 1 (BuHV-1) is a virus that belongs to the Varicellovirus genus within the Alphaherpesvirinae subfamily. While BuHV-1 infections in water buffaloes (Bubalus bubalis) are often subclinical, clinical manifestations have been reported. This study provides complete genome sequences of five BuHV-1 strains isolated in Argentina, marking the first genomic characterization of BuHV-1 from the Americas. Phylogenetic reconstructions based on whole-genome and coding sequences, along with analyses of glycoproteins C, D, and E, identified a distinct clade and divergent strains. Comparative genomic analyses with publicly available BuHV-1 and Bovine alphaherpesvirus 5 (BoHV-5) sequences showed nucleotide divergence of up to 1.3% among BuHV-1 strains, indicating significant intraspecific genetic diversity. Cross-neutralization assays revealed variable relationships between BuHV-1 and BoHV-5 strains. Some Argentinian BuHV-1 strains exhibited significant antigenic subtype differences compared to Bovine alphaherpesvirus 1 (BoHV-1). Recombination analyses uncovered events between BuHV-1 and bovine herpesviruses, suggesting a complex evolutionary history within mixed farming systems. The findings indicate that the monophyletic BuHV-1 clade, including the reference BuHV-1 isolate, is representative of the BuHV-1 species. The remaining strains, provisionally classified as BuHV-1 indeterminate (BuHV-1i), can be categorized based on specific clinical and antigenic properties. The identified heterogeneity has significant implications for diagnostic accuracy, vaccine development, and disease management strategies in buffalo populations worldwide. Full article

Background/Objectives: Paclitaxel (PTX) faces clinical limitations in melanoma treatment due to poor solubility, P-glycoprotein (P-gp)-mediated efflux, and systemic toxicity. This study aimed to develop PTX-loaded mesoporous silica nanoparticles (PS), which would be co-administered with curcumin (CUR) and D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) to enhance intracellular accumulation and improve anti-tumor activity. CUR and TPGS were integrated with PS to inhibit P-gp-mediated PTX-efflux, to enhance the intracellular accumulation of PTX, and to improve anti-tumor activity in B16F10 cells. Methods: The physicochemical properties of PS were analyzed using standard characterization methods. The antitumor activity of PS co-administered with CUR and TPGS was evaluated using two-dimensional (2D) culture and three-dimensional (3D) spheroid assays, and also assessed in B16F10 tumor-bearing mice. The therapeutic mechanism of the PS combination was compared using apoptosis and microtubule disruption through flow cytometry and confocal microscopy. The pharmacokinetics and biodistribution of the PS combination were compared in B16F10 tumor-bearing mice. Results: PS formulations exhibited amorphous transformation with an approximate particle size of 200 nm. PS co-administered with CUR and TPGS reduced the IC₅₀ to 178.7 nM compared with 283.3 nM for free PTX in B16F10 melanoma cells and achieved significant tumor growth inhibition in B16F10 melanoma spheroid culture. The intracellular accumulation of PTX correlated with its therapeutic efficacy. Flow cytometry revealed a significant induction of both early and late apoptosis in cells treated with the PS + CUR + TPGS combination, while confocal imaging confirmed enhanced microtubule disruption. In B16F10 tumor-bearing mice, PS co-administered with CUR and TPGS demonstrated higher and selective distribution of PTX into tumor tissue without affecting systemic exposure of PTX in B16F10-xenografted mice. Conclusions: PS + CUR + TPGS combination enhanced PTX delivery by improving solubility and enhancing distribution to tumor tissue through P-gp inhibition, thereby increasing its therapeutic potential. The combination of CUR and TPGS offers synergistic apoptosis induction and microtubule disruption. Thus, the PS + CUR + TPGS combination represents a promising approach for treating drug-resistant melanomas. Full article

Background/Objectives: This study was conducted to analyze the associations between vascular endothelial growth factor (VEGF) serum concentrations and immunological biomarkers, inflammatory parameters, classical atherosclerosis risk factors, and cardiovascular manifestations in systemic lupus erythematosus (SLE) patients. Methods: The project included 83 individuals suffering from SLE, with 20 healthy individuals as controls. The serum levels of VEGF were determined through the ELISA method using R&D Systems tests. Laboratory markers, autoantibody profiles, traditional atherosclerotic risk factors, and organ manifestations were evaluated. Atherosclerotic changes were determined based on several indices including carotid intima-media thickness, ankle-brachial index and high resistance index assessments. Results: The reference range of serum VEGF concentrations was established based on the 25th and 75th percentiles obtained in the controls. High VEGF levels were significantly correlated with the presence of selected anti-phospholipid antibodies such as anti-prothrombin (OR = 10.7; 95%CI: 2.1–53.4) and anti-beta2 glycoprotein I (OR = 3.5; 95%CI: 1.1–10.8), as well as cardiac disorders (OR = 8.0; 95%CI: 1.6–39.5). On the other hand, low concentrations of VEGF were significantly related to lower frequencies of anti-double-stranded DNA antibodies (OR = 0.31; 95%CI: 0.11–0.91) and anti-endothelial cell antibodies (OR = 0.30; 95%CI: 0.11–0.85). Patients with low VEGF levels showed significantly reduced risks of atherosclerotic lesions (OR = 0.24; 95%CI: 0.04–0.99) and vasculitis development (OR = 0.17; 95%CI = 0.03–0.91). Conclusions: In conclusion, VEGF’s pathogenetic role in SLE and SLE-related atherothrombosis is manifested in close correlation with aPLs which may enhance their direct impact on endothelium. High VEGF levels are helpful for identifying cardiovascular risk in patients, while low concentrations indicate lower disease activity, as well as a lower risk of organ involvement. Full article

Major Depressive Disorder (MDD) is increasingly linked to disruptions in blood-brain barrier (BBB) integrity, contributing to neuroinflammation and impaired brain homeostasis. While traditional antidepressant therapies often fail to achieve full remission, growing evidence suggests that specific dietary compounds may offer novel avenues for restoring BBB function and improving mental health outcomes. This review explores the potential of selected nutrients—omega-3 fatty acids, vitamin D, sulforaphane, fucoidan, and urolithins—to modulate BBB integrity through anti-inflammatory, antioxidant, and transporter-regulatory mechanisms. These compounds act by reinforcing tight junctions, reducing matrix metalloproteinase activity, and modulating efflux transporters such as P-glycoprotein. Although current evidence is largely preclinical, the mechanistic insights provided in this review support the rationale for integrating nutritional strategies into the management of MDD. Future clinical studies are needed to validate these findings and develop biomarker-driven approaches for targeting the BBB in nutritional interventions for psychiatric disorders. Full article