Takotsubo syndrome (TTS) is an acute and reversible form of heart failure characterized by transient left ventricular dysfunction, typically triggered by acute stress stimuli. TTS, also referred to as “stress cardiomyopathy”, may paradoxically be triggered not only by negative stressors but also by intense positive emotional experiences. Interestingly, TTS was sharply incremented during and following the COVID-19 pandemic. Despite increased clinical recognition, reliable biomarkers for early diagnosis and prognosis remains limited. Oxidative stress is increasingly recognized as a key mechanism in TTS, acting downstream of sympathetic overactivation, thus contributing to myocardial stunning, endothelial dysfunction, and inflammation. In this context, extracellular vesicles (EVs) have emerged as key mediators of intercellular communication and as potential circulating biomarkers, as they reflect the molecular state of their cells of origin. In this review, we summarize the current diagnostic approaches for TTS, including the InterTAK Diagnostic Score, imaging gold standards, and emerging biomarkers such as circulating miRNAs and EV cargo associated with TTS. Furthermore, we critically examine the mechanistic interplay between oxidative stress and EVs in TTS, highlighting translational perspectives and future directions for integrating EV-based biomarkers into personalized clinical management.

Abstract Small extracellular vesicles (sEVs) are critical mediators of tumor microenvironment communication, largely through the selective transfer of microRNAs (miRNAs) that reprogram recipient cells. Active miRNA sorting into sEVs depends on RNA‑binding proteins (RBPs), sequence determinants, and RNA modifications. Here, a functional interplay between the RBP SYNCRIP and N6‑methyladenosine (m6A) RNA methylation controlling miRNA loading into hepatocellular carcinoma (HCC)‑derived sEVs has been disclosed. It is reported that (i) METTL3 (Methyltransferase-like-3)‑dependent m6A modification is required for efficient binding of SYNCRIP to specific miRNAs, thereby enabling their selective incorporation into sEVs; (ii) silencing of SYNCRIP markedly reshapes the sEV miRNA-cargo and impairs the ability of HCC‑derived sEVs to induce epithelial-to-mesenchymal transition (EMT) in non‑tumorigenic hepatocytes. Notably, (iii) depletion of METTL3 produces an even stronger effect, indicating that m6A methylation represents an upstream and essential determinant of SYNCRIP‑mediated miRNA export. Mechanistically, the data identify SYNCRIP as an m6A‑dependent miRNA reader, adding epitranscriptomic regulation to sequence‑based miRNA sorting into sEVs. Functionally, disruption of this interaction attenuates sEV‑driven EMT and pro‑tumorigenic signaling. Collectively, these findings uncover a novel regulatory axis governing sEV miRNA cargo selection and highlight the m6A–SYNCRIP interplay as a potential therapeutic target to interfere with sEV‑mediated tumor progression and metastasis.

Gynecological cancers remain a major global health burden due to their high incidence, molecular heterogeneity, and frequent resistance to conventional therapies. Beyond well-established genetic alterations and targeted treatments, growing attention has been directed toward the role of cancer stem cells (CSCs), a rare tumor subpopulation with self-renewal, differentiation, and tumor-initiating capacities. CSCs are sustained by a specialized microenvironment, the cancer stem cell niche, where growth factors, cytokines, hypoxia, and stromal interactions converge to promote stemness, chemoresistance, and metastatic potential. In breast cancer, signaling axes such as EGFR, IGF, TGFβ, and HGF/c-Met critically regulate CSC expansion, particularly in aggressive subtypes like triple-negative tumors. In ovarian cancer, factors including HGF, VEGFA, IGF, and stromal-derived BMPs drive CSC plasticity and contribute to relapse after platinum therapy. Endometrial CSCs are supported by pathways involving TGFβ, BMP2, and Netrin-4/c-Myc signaling, while in cervical cancer, VEGF, IGF-1, Gremlin-1, and TGFβ-mediated circuits enhance stem-like phenotypes and drug resistance. Cytokine-driven inflammation, especially via IL-3, IL-6, IL-8, IL-10, and CCL5, further fosters CSC survival and immune evasion across gynecologic malignancies. Preclinical studies demonstrate that targeting growth factors and cytokine signaling, through monoclonal antibodies, receptor inhibitors, small molecules, or cytokine modulation, can reduce CSC frequency, restore chemosensitivity, and enhance immunotherapy efficacy. This review highlights the interplay between CSCs, growth factors, and cytokines as central to tumor progression and relapses, emphasizing their translational potential as therapeutic targets in precision oncology for gynecological cancers.

Coronary artery disease (CAD) is a leading cause of death worldwide, encompassing a broad spectrum of pathological conditions ranging from chronic to acute coronary syndromes. It underlies complex biological mechanisms, among which an emerging role is played by extracellular vesicles (EVs). EVs are non-replicable cell-derived particles enclosed by lipid bilayers acting as mediators of cellular interactions. In the past two decades, there has been a growing interest in EVs as potential diagnostic, prognostic and therapeutic tools in cardiovascular disease. We reviewed the most recent studies on circulating EVs in CAD with a particular focus on their role in biomarker discovery. Our aim was to evaluate the feasibility of translating these findings into routine clinical practice. To this end, we underlie the development and application of integrated indicators, referred to as “Bioscores”, which combine clinical, laboratory, and molecular data to enhance diagnostic and prognostic accuracy. We briefly discuss the opportunity and pitfalls related to the emerging use of Machine Learning (ML) algorithms. Moreover, we highlight that further investigation of mechanistic pathways is required beyond the initially predicted associations generated by in silico studies. Finally, we analyzed the key limitations, challenges, and unmet needs in the field, including small and unrepresentative sample sizes, a lack of external validation, overlapping and often contradictory effects on targeted pathways, difficulties in standardizing EV isolation and characterization methods, as well as concerns regarding affordability and clinical reliability.

Reliable predictive biomarkers to reduce unnecessary coronary angiograms (CAGs) in non-ST-segment elevation myocardial infarction (NSTEMI) and unstable angina (UA) patients displaying high-risk features are still lacking. Here, we show that profiling patient-derived circulating extracellular vesicles (EVs) can not only improve their risk stratification but also reduce unnecessary CAGs. Analysis of EVs and their miR cargo revealed that CD62p+EVs enriched in miR-130a-3p correlated with the absence of non-critical coronary artery disease (CAD). Proteomic analysis identified nine proteins differentially enriched in patients with or without critical-CAD (NO CAD), irrespective of their diagnosis. Multivariate analysis identified miR-130a-3p (odds ratio [OR]:0.35 [0.19-0.67]), phospholipid transfer protein (OR 0.96 [0.94-0.98]), and subunit beta of mitochondrial trifunctional enzyme (OR:0.96 [0.94-0.98]) as predictors of NO CAD. Furthermore, EV-miR-130a-3p enrichment predicted the absence of multivessel disease (OR:0.46 [0.23-0.90]). These findings establish EV profiling as a valuable tool for stratifying and optimizing the clinical management of patients with acute coronary syndrome.

Bispecific antibodies (bsAbs) have emerged as one of the most versatile innovations in immunotherapy, capable of simultaneously engaging two distinct epitopes within a single molecule and thereby expanding the functional repertoire of conventional monoclonal antibodies. Their capacity to integrate checkpoint blockade, co-stimulatory activation and cytokine modulation renders them particularly attractive in conditions driven by dysregulated or redundant immune pathways, including cancer, autoimmunity, chronic inflammation and infectious diseases. Technological advances such as knobs-into-holes, dual-affinity retargeting (DART) constructs and IgG-like asymmetric designs have refined stability, pharmacokinetics and manufacturability, enabling clinical translation beyond oncology. Nevertheless, significant challenges remain, including immunogenicity, cytokine release syndrome, neurotoxicity and adaptive resistance mediated by antigen modulation or tissue microenvironmental adaptation. To mitigate these, innovative approaches, ranging from protease-activatable constructs and Fc engineering to albumin-binding fusion proteins and bispecific antibody-drug conjugates, are under active investigation. In addition, bsAbs are being integrated with other immunomodulatory strategies such as CAR-T cells, therapeutic vaccines and checkpoint inhibitors, offering the potential for synergistic benefit across diverse immune-mediated diseases. In this review, we chart the trajectory of bsAb development from molecular design to clinical translation in cancer and immune regulation. We highlight structural optimisation, pharmacokinetic tuning and mechanisms of immune regulation, aiming to provide a framework for their rational use in reshaping immune response in cancer and beyond.

Triple negative breast cancer (TNBC) remains one of the most aggressive subtypes of cancer with a poor prognosis and limited treatment options. Building on our previous findings of elevated Interleukin-3-Receptor-α (IL-3Rα) expression in TNBC, this study investigates the mechanisms underpinning IL-3-mediated actions in TNBC. GEO database (GSE25066) was interrogated to evaluate the expression of IL-3. RNAseq data were acquired from the TCGA-BRCA (Breast Carcinoma) project. Seven TNBC cell lines were used to validate the expression of IL-3 by ELISA assay. Chromatin immunoprecipitation assay was performed to evaluate the binding of STAT5A to the miR-155-5p promoter in TNBC cells. FACS analysis and ALDH activity were performed to evaluate the expansion of ALDH-1A1 + and CD44high/CD24low subpopulations. Mammosphere formation efficiency (MFE) was evaluated using the standard assay, while chemoresistance by applying the incucyte cell viability assay. miR155-5p silencing served to validate the expression of all target proteins both in vitro and in vivo. Bioinformatic analysis of breast cancer patient gene datasets revealed significant upregulation of the IL-3 gene in TNBC patient samples compared to the non-TNBC group (GEO: p = 0.004: TCGA p = 2.7e−30 respectively). We also found that TNBC cells secrete IL-3, which activates STAT5A promoting miR-155-5p expression by binding to its promoter in TNBC cells. Correlation analysis based on TCGA-BRCA confirmed elevated miR-155-5p levels in TNBC compared to non-tumoral tissues (p = 2.1e−33) and non-TNBC (p = 6.5e−30), with positive correlations between the IL-3 and miR-155-5p (r = 0.157, p < 0.001), as well as between miR-155-5p and miR-155-3p and STAT5A (r = 0.250, p = 0.002; r = 0.245, p < 0.005 respectively). Functional studies demonstrated that miR-155-5p downregulates programmed cell death 4, APC, and GSK-3β, enhancing β-catenin nuclear translocation and c-myc expression. Silencing miR-155-5p reversed all these effects. IL-3, via miR-155-5p, also drives ALDH-1A1 + and CD44high/CD24low subpopulation expansion and ALDH activity, enhances MFE and chemoresistance. Notably, blocking IL-3 impaired MFE, suggesting an autocrine loop sustaining IL-3 action in TNBC. In vivo, IL-3 promoted tumour growth, β-catenin activity, and metastasis, while miR-155-5p silencing mitigated these effects. Overall, our results underscore the crucial role of IL-3 in tumour progression, thereby advocating IL-3/IL-3Rα axis targeting as a promising therapeutic approach for TNBC.

A cutting-edge approach in cell-based immunotherapy for combating resistant cancer involves genetically engineered chimeric antigen receptor T (CAR-T) lymphocytes. In recent years, these therapies have demonstrated effectiveness, leading to their commercialization and clinical application against certain types of cancer. However, CAR-T therapy faces limitations, such as the immunosuppressive tumour microenvironment (TME) that can render CAR-T cells ineffective, and the adverse side effects of the therapy, including cytokine release syndrome (CRS).Extracellular vesicles (EVs) are a diverse group of membrane-bound particles released into the extracellular environment by virtually all cell types. They are essential for intercellular communication, transferring cargoes such as proteins, lipids, various types of RNAs, and DNA fragments to target cells, traversing biological barriers both locally and systemically. EVs play roles in numerous physiological processes, with those from both immune and non-immune cells capable of modulating the immune system through activation or suppression. Leveraging this capability of EVs to enhance CAR-T cell therapy could represent a significant advancement in overcoming its current limitations.This review examines the current landscape of CAR-T cell immunotherapy and explores the potential role of EVs in augmenting its therapeutic efficacy.

Fibrosis is a marker of chronic kidney disease (CKD) and consists of the accumulation of the extracellular matrix (ECM) components, causing the progressive deterioration of kidney function. Human liver stem cells (HLSCs) have anti-fibrotic activity, and HLSC-derived extracellular vesicles (EVs) mediate this effect. Herein, we evaluated the ability of HLSC-EVs to reverse renal and cardiac alterations in a murine model of partial nephrectomy (PNx) that mimics human CKD development. Furthermore, we investigated the contribution of extracellular matrix remodeling-related proteases to the anti-fibrotic effect of HLSC-EVs. PNx was performed by ligation of both poles of the left kidney, followed one week later by the removal of the right kidney. EV treatment started 4 weeks after the nephrectomy, when renal and cardiac alternations were already established, and mice were sacrificed at week eight. HLSC-EV treatment improved renal function and morphology, significantly decreasing interstitial fibrosis, glomerular sclerosis, and capillary rarefaction. This improvement was confirmed by the decreased expression of pro-fibrotic genes. Moreover, EV treatment improved cardiac function and reduced cardiac fibrosis. HLSC-EVs shuttled different proteases with ECM remodeling activity, and matrix metalloproteinase 1 (MMP-1) was involved in their anti-fibrotic effect on renal tissue. HLSC-EV treatment interferes with CKD development and ameliorates cardiomyopathy in PNx mice.

Herpes zoster ophthalmicus results from the reactivation of the latent varicella zoster virus, affecting the first branch of the trigeminal nerve. In 20–70% of cases, Zoster Ophthalmicus can lead to ocular involvement, affecting various orbital structures. Orbital myositis is a rare but severe complication of herpes zoster ophthalmicus. We present a case of a 52-year-old man with no significant medical history who developed zoster-associated right ocular myositis and dacryocystitis. He was treated with intravenous acyclovir and oral steroids. A review of the literature identified 29 patients across 19 studies. The median age was 61 years, with a slight female predominance. In 55% of cases, the patients had no notable medical history. The most common presentation of myositis involved all oculomotor muscles. There were 22 cases who were treated with intravenous antiviral therapy and 19 received steroids. A full resolution of symptoms was achieved in 51.7% of patients. Zoster-related orbital myositis is a rare complication that should be considered even in immunocompetent individuals. It may occur either before or after the appearance of a vesicular rash. Magnetic resonance imaging is the preferred radiological exam for assessing orbital involvement. Intravenous antiviral therapy should be started within 72 h of symptom onset, and its combination with systemic corticosteroids appears to be an effective treatment for zoster-related ocular myositis.

miR-148b reduces liver and lung metastasis formation

miR-214 and miR-148b affect migration and invasion ability

COVID-19 is characterized by an excessive inflammatory response and macrophage hyperactivation, leading, in severe cases, to alveolar epithelial injury and acute respiratory distress syndrome. Recent studies have reported that SARS-CoV-2 spike (S) protein interacts with bacterial lipopolysaccharide (LPS) to boost inflammatory responses in vitro, in macrophages and peripheral blood mononuclear cells (PBMCs), and in vivo. The hypothalamic hormone growth hormone-releasing hormone (GHRH), in addition to promoting pituitary GH release, exerts many peripheral functions, acting as a growth factor in both malignant and non-malignant cells. GHRH antagonists, in turn, display potent antitumor effects and antinflammatory activities in different cell types, including lung and endothelial cells. However, to date, the antinflammatory role of GHRH antagonists in COVID-19 remains unexplored. Here, we examined the ability of GHRH antagonist MIA-602 to reduce inflammation in human THP-1-derived macrophages and PBMCs stimulated with S protein and LPS combination. Western blot and immunofluorescence analysis revealed the presence of GHRH receptor and its splice variant SV1 in both THP-1 cells and PBMCs. Exposure of THP-1 cells to S protein and LPS combination increased the mRNA levels and protein secretion of TNF-α and IL-1β, as well as IL-8 and MCP-1 gene expression, an effect hampered by MIA-602. Similarly, MIA-602 hindered TNF-α and IL-1β secretion in PBMCs and reduced MCP-1 mRNA levels. Mechanistically, MIA-602 blunted the S protein and LPS-induced activation of inflammatory pathways in THP-1 cells, such as NF-κB, STAT3, MAPK ERK1/2 and JNK. MIA-602 also attenuated oxidative stress in PBMCs, by decreasing ROS production, iNOS and COX-2 protein levels, and MMP9 activity. Finally, MIA-602 prevented the effect of S protein and LPS synergism on NF-кB nuclear translocation and activity. Overall, these findings demonstrate a novel antinflammatory role for GHRH antagonists of MIA class and suggest their potential development for the treatment of inflammatory diseases, such as COVID-19 and related comorbidities.

Current therapeutic approaches for chronic venous ulcers (CVUs) still require evidence of effectiveness. Diverse sources of extracellular vesicles (EVs) have been proposed for tissue regeneration, however the lack of potency tests, to predict in-vivo effectiveness, and a reliable scalability have delayed their clinical application. This study aimed to investigate whether autologous serum-derived EVs (s-EVs), recovered from patients with CVUs, may be a proper therapeutic approach to improve the healing process. A pilot case-control interventional study (CS2/ 1095/0090491) has been designed and s-EVs recovered from patients. Patient eligibility included two or more distinct chronic lesions in the same limb with 11 months as median persistence of active ulcer before enrollment. Patients were treated three times a week, for 2 weeks. Qualitative CVU analysis demonstrated that s-EVs-treated lesions displayed a higher percentage of granulation tissue compared to the control group (Sham) (s-EVs 3 out of 5: 75-100 % vs Sham: none), further confirmed at day 30. s-EVs-treated lesions also displayed higher sloughy tissue reduction at the end of treatment even increased at day 30. Additionally, s-EV treatment led to a median surface reduction of 151 mm(2) compared to 84 mm(2) in the Sham group, difference even more evident at day 30 (s-EVs 385 mm(2) vs Sham 106 mm(2) p = 0.004). Consistent with the enrichment of transforming growth factor-81 in s-EVs, histological analyses showed a regenerative tissue with an increase in microvascular proliferation areas. This study first demonstrates the clinical effectiveness of autologous s-EVs in promoting the healing process of CVUs unresponsive to conventional treatments.

miR-214 and miR-148b sponge sequences

Non-healing wound- and tissue-injury are commonly experienced worldwide by the aging population. The persistence of disease commonly leads to tissue infection, resulting in severe clinical complications. In the last decade, extracellular vesicles (EVs) have been considered promising and emergent therapeutic tools to improve the healing processes. Therefore, efforts have been directed to develop a cell-free therapeutic platform based on EV administration to orchestrate tissue repair. EVs derived from different cell types, including fibroblast, epithelial, and immune cells are recruited to the injured sites and in turn take part in scar formation. EVs are nano-sized particles containing a heterogeneous cargo consisting of lipids, proteins, and nucleic acids protected from degradation by their lipid bilayer. Noteworthy, since EVs have natural biocompatibility and low immunogenicity, they represent the ideal therapeutic candidates for regenerative purposes. Indeed, EVs are released by several cell types, and even if they possess unique biological properties, their functional capability can be further improved by engineering their content and functionalizing their surface, allowing a specific cell cargo delivery. Herein, we provide an overview of preclinical data supporting the contribution of EVs in the repair and regenerative processes, focusing on different naïve EV sources, as well as on their engineering, to offer a scalable and low-cost therapeutic option for tissue repair.

miR-214 inhibition and miR-148b overexpression impair melanoma cell extravasation

The correlation between diabetes mellitus and infectious diseases is widely recognized. DM patients are characterized by the impaired function of the immune system. This translates into the occurrence of a variety of infections, including urinary tract, skin and surgical site infections, pneumonia, tuberculosis, and, more recently, SARS-CoV-2. Hyperglycemia has been identified as a relevant factor contributing to unfavorable outcomes in hospitalized patients including SARS-CoV-2 patients. Several studies have been performed proving that to maintain the proper and stringent monitoring of glycemia, a balanced diet and physical activity is mandatory to reduce the risk of infections and their associated complications. This review is focused on the mechanisms accounting for the increased susceptibility of DM patients to infections, with particular attention to the impact of newly introduced hypoglycemic drugs in sepsis management.

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