Unverricht-Lundborg disease (ULD), also known as progressive myoclonic epilepsy 1 (EPM1), is a rare autosomal recessive neurodegenerative disorder characterized by a complex symptomatology that includes action- and stimulus-sensitive myoclonus and tonic-clonic seizures. The main cause of the onset and development of ULD is a repeat expansion of a dodecamer sequence localized in the promoter region of the gene encoding cystatin B (CSTB), an inhibitor of lysosomal proteases. Although this is the predominant mutation found in most patients, the physio-pathological mechanisms underlying the disease complexity remain largely unknown. In this work, we used patient-specific iPSCs and their neuronal derivatives to gain insight into the molecular and genetic machinery responsible for the disease in two Italian siblings affected by different phenotypes of ULD. Specifically, fragment length analysis on amplified CSTB promoters found homozygous status for dodecamer expansion in both patients and showed that the number of dodecamer repeats is the same in both. Furthermore, the luciferase reporter assay showed that the CSTB promoter activity was similarly reduced in both lines compared to the control. This information allowed us to draw important conclusions: (1) the phenotypic differences of the patients do not seem to be strictly dependent on the genetic mutation around the CSTB gene, and (2) that some other molecular mechanisms, not yet clearly identified, might be taken into account. In line with the inhibitory role of cystatin B on cathepsins, molecular investigations performed on iPSCs-derived neurons showed an increased expression of lysosomal cathepsins (B, D, and L) and a reduced expression of CSTB protein. Intriguingly, the increase in cathepsin expression does not appear to be correlated with the residual amount of CSTB, suggesting that other mechanisms, in addition to the regulation of cathepsins, could be involved in the pathological complexity of the disease.

Background/Objectives: Platelet-rich plasma (PRP) has been proposed as a biological augmentation strategy in the surgical repair of acute Achilles tendon rupture (ATR). However, clinical evidence remains heterogeneous, and its impact on structural and functional recovery is unclear. This review synthesizes comparative clinical evidence on PRP augmentation in surgical acute ATR repair. Methods: A comprehensive review of comparative clinical studies was conducted using PubMed, MEDLINE, Scopus, and Cochrane Central databases. Seven studies, including three randomized controlled trials, met the inclusion criteria, totaling 207 patients. Methodological quality was assessed using the Modified Newcastle-Ottawa Scale and Cochrane Risk of Bias tool. Results: Several studies reported early functional improvements with PRP. Zou et al. found better range of motion at 24 months (p < 0.001). Sánchez et al. reported faster recovery of range of motion (7 vs. 11 weeks) and earlier return to running (11 vs. 18 weeks). Hung et al. observed improved range of motion at 6 months, without differences at 24 months (ATRS 92.9 vs. 92.7). Conversely, randomized trials by Yasui, Schepull, and De Carli showed no significant long-term differences in functional outcomes. Conclusions: PRP may enhance early recovery after surgical acute ATR repair, but consistent long-term superiority has not been demonstrated. Heterogeneity in PRP preparation and administration likely contributes to conflicting findings. Further standardized trials are required to define its clinical role.

Background/Objectives: Osteonecrosis of the femoral head (ONFH) is a progressive condition characterized by bone necrosis, impaired vascularization, and immune dysregulation, often resulting in femoral head collapse. Effective strategies to halt disease progression are limited. Extracellular vesicles (EVs), including exosomes and microvesicles, mediate intercellular communication and influence osteogenesis, angiogenesis, and immune responses. This review summarizes current evidence on EVs in ONFH and their translational potential. Methods: A structured narrative review of PubMed, Scopus, Web of Science, and Cochrane Central databases was conducted, including in vitro, preclinical, and clinical studies on EVs in ONFH. Data on EV sources, molecular cargo, signaling pathways, functional effects, and translational implications were qualitatively synthesized. No pooled statistical analysis was performed because the extracted data were heterogeneous. Bioinformatic analyses such as Gene Ontology, KEGG enrichment, and protein–protein interaction networks were also summarized. Results: In vitro, EVs from bone marrow mesenchymal stem cells, endothelial cells, and M2 macrophages modulate osteogenic differentiation, angiogenesis, and inflammation. Preclinical studies demonstrate that EV administration reduces femoral head necrosis, improves trabecular structure, and enhances neovascularization. Clinical studies have identified EV-associated molecules (SAA1, C4A, RPS8) linked to disease stage and the risk of femoral head collapse. Bioinformatic analyses connect EV cargo to pathways regulating bone formation, vascularization, immunity, and metabolism. Conclusions: EVs appear to play key roles in ONFH pathogenesis and may represent promising candidates for diagnostic and therapeutic applications. However, current clinical evidence remains limited and requires validation in larger studies. Nonetheless, heterogeneity and limited clinical data require standardized, longitudinal studies to validate their translational relevance.

Background: Osteoarthritis (OA) of the knee is a degenerative disorder characterized by cartilage degradation, synovial inflammation, and structural remodeling. Synovial fluid (SF) biomarkers may improve diagnosis, staging, and patient stratification. Methods: Following PRISMA guidelines, a systematic search of PubMed and Scopus (2015-2025) was conducted. Human studies analyzing SF with proteomic techniques (LC-MS/MS, SWATH-MS, ELISA) were included. Extracted data were classified by OA stage, sample type, proteomic platform, and identified biomarkers. Functional enrichment was performed with ShinyGO, and protein-protein interaction (PPI) analysis with STRING (v12.0). Results: Seven studies met the inclusion criteria. Reported biomarkers included Cathepsin G (CTSG), angiotensinogen (AGT), periostin (POSTN), haptoglobin (HP), complement components, and matrix-related proteins such as ADAMTS4 and LYVE-1, which are involved in extracellular matrix remodeling, inflammation, and joint tissue homeostasis. Functional annotation revealed enrichment in glycosaminoglycan binding, complement cascades, and redox pathways. PPI analysis identified central nodes including COL1A1, ACAN, COMP, and POSTN, together with matrix-degrading enzymes such as MMP1, MMP3, and MMP13, highlighting tightly connected extracellular matrix remodeling processes in OA. Conclusion: This review highlights reproducible SF biomarkers with diagnostic and prognostic potential in knee OA. Integrated proteomic and network analysis reinforces the multifactorial nature of OA and suggests key molecular targets. Translationally, a consistent biomarker signature could support early detection, more precise staging, and personalized management, enabling biomarker-guided diagnostics, targeted therapies, and the integration of precision medicine into OA care.

Rotator cuff disorders are among the most common causes of shoulder pain and dysfunction, primarily driven by chronic inflammation and degenerative changes in tendon tissue. These alterations lead to progressive structural damage and compromised function. In recent years, proteomic profiling has emerged as a promising strategy for identifying molecular signatures associated with disease mechanisms and potential translational applications. A systematic review was conducted using PubMed and Scopus databases, targeting studies published between 2015 and 2024. Included studies focused on proteomic biomarker analysis in synovial fluid, and blood from patients affected by rotator cuff disorders. Methodological quality and risk of bias were evaluated using the Newcastle-Ottawa Scale for observational studies and the RoB 2.0 tool for randomized controlled trials. Seven studies were found to meet the inclusion criteria. Among the most consistently reported proteins were matrix metalloproteinase-1, matrix metalloproteinase-13, interleukin-1β, interleukin-6, and transforming growth factor-β1, with a predominant presence in synovial fluid samples. Enrichment analyses pointed to their involvement in inflammatory cascades, extracellular matrix turnover, and neovascularization. Network analysis of protein-protein interactions highlighted interleukin-6 and matrix metalloproteinase-13 as central nodes, indicating a pivotal role in modulating disease progression. The most reported biomarkers, such as matrix metalloproteinase-1, matrix metalloproteinase-13, interleukin-1β, interleukin-6, and transforming growth factor-β1, are associated primarily with inflammatory signaling and extracellular matrix remodeling, highlighting their involvement in molecular pathways related to rotator cuff disease progression and tissue degeneration. Gene Ontology enrichment and KEGG pathway analyses further revealed that these proteins are significantly involved in biological processes relevant to tendon degeneration, including cytokine-mediated signaling, the wound response, and ECM organization. The identified biomarkers, particularly interleukin-6, matrix metalloproteinase-1, matrix metalloproteinase-13, and transforming growth factor-β1, may represent candidates for inclusion in future multi-analyte diagnostic panels, pending rigorous clinical validation. However, at present these applications remain hypothetical. Further large-scale, standardized, and longitudinal studies are required to validate their incremental value beyond imaging and clinical evaluation before any clinical translation can be considered. This systematic review synthesizes current evidence on proteomic biomarkers detectable in the synovial fluid and blood of patients with rotator cuff disorders, highlighting candidate molecules (e.g., IL-6, MMP-1, MMP-13, TGF-β1) that are mechanistically linked to inflammation and extracellular matrix remodeling. While these markers are not disease-specific, they may have translational utility as components of multi-analyte panels for (1) stratifying disease severity, (2) monitoring biological response to conservative or surgical treatments, and (3) potentially informing future strategies for disease stratification and personalized therapeutic approaches. Real-world clinical translation will require standardized sample collection and assay protocols, analytical validation (targeted MS or clinical immunoassays), and prospective studies to define diagnostic thresholds and incremental value over imaging and clinical assessment.

The progressive loss of dopaminergic identity in midbrain neurons is a hallmark of Parkinson’s disease (PD), contributing to synaptic dysfunction and neurodegeneration. While a subset of PD cases is linked to genetic mutations, the majority are sporadic (sPD) and of unknown etiology. Current therapies offer only symptomatic relief and do not prevent neurodegeneration, underscoring the urgent need for disease-modifying strategies targeting actionable molecular pathways. Here, we used human induced pluripotent stem cell (hiPSC)-derived midbrain dopaminergic neurons (mDAs) from sporadic PD patients to investigate early alterations in neuronal identity, plasticity, and survival. We found that PD-derived mDAs exhibit upregulation of phosphorylated α-synuclein, marked reductions in dopaminergic markers (TH, NURR1), deficient dopamine handling, and impaired synaptogenesis. Transcriptomic and protein analyses revealed sustained activation of apoptotic caspases (caspase-3, -7) and downregulation of the PKA–CREB–BDNF signaling axis, which underpins dopaminergic differentiation and synaptic maturation. Pharmacological inhibition of caspases with Q-VD-OPh restored pCREB, BDNF, and downstream dopaminergic markers, leading to morphological recovery and functional synaptic rescue. Inhibition of PKA with H89 abrogated these effects, positioning the caspase–PKA–CREB cascade as a critical regulator of dopaminergic identity in PD neurons. These findings define a novel non-apoptotic role for caspases in disrupting the transcriptional program of mDAs and identify a druggable pathway capable of rescuing key aspects of dopaminergic function in a patient-derived cellular model. This work provides a mechanistic rationale for targeting caspase signaling in early-stage PD.