Search Results (169)

The interindividual phenotypic heterogeneity in Alpha-1 Antitrypsin Deficiency (AATD), despite a shared genetic etiology (the Z-allele of SERPINA1), is explained by the interaction of dual pathogenic mechanisms (gain-of-function vs. loss-of-function), additional genetic modifiers, and environmental or metabolic factors. Building on recent evidence suggesting divergent disease trajectories, we investigated whether pulmonary and hepatic impairments represent coupled manifestations or independent clinical dimensions within a large European cohort. Methods: This international multicenter study utilized the European Alpha-1 Research Collaboration (EARCO) registry (n = 1217). Pulmonary and hepatic severities were quantified using concurrent 0.0–10.0 composite indices. Independence was evaluated via partial Spearman correlations, multivariable multinomial regression, and geometric mapping across a continuous phenotypic space. Results: Cross-domain correlations between respiratory metrics and liver stiffness were near zero (r = −0.03), demonstrating statistical independence. Phenotypic dominance classification isolated distinct profiles; the lung-dominant group exhibited a higher age (57.0 vs. 54.0 years; p < 0.001) and tobacco exposure, while the liver-dominant group registered a higher body mass index (25.8 vs. 24.4 kg/m²; p < 0.001). Multivariable models identified age (OR 1.03; 95% CI 1.02–1.05) and smoking as independent predictors of lung dominance, whereas body mass index was independently associated with liver dominance (OR 1.04; 95% CI 1.01–1.07). Geometric mapping revealed advanced disease clusters at orthogonal margins rather than forming a systemic continuum. Conclusions: Hepatic and pulmonary impairments in AATD operate as independent clinical dimensions modulated by distinct metabolic and environmental factors. Risk stratification must transition toward organ-specific prognostic models. Full article

Alpha-1 antitrypsin deficiency (AATD) is a genetically heterogeneous disorder with well-established pulmonary and hepatic manifestations; however, the clinical significance of rare compound heterozygous SERPINA1 variants remains incompletely defined. We report the case of a 61-year-old never-smoking woman with chronically elevated liver transaminase who was found to carry a compound heterozygous SERPINA1 genotype (PI*V/M_procida) previously classified as non-polymerogenic and not previously associated with hepatic inclusions. This case expands the phenotypic spectrum of AATD and highlights the importance of considering SERPINA1 genotyping in adults with unexplained chronic transaminase elevation, while raising clinically relevant questions regarding surveillance and management in atypical AATD phenotypes. Full article

Alzheimer’s disease is a progressive neurodegenerative disorder in which early detection remains limited by the cost and invasiveness of positron emission tomography and cerebrospinal fluid testing. We evaluated whether plasma proteomic profiles could distinguish amyloid PET-positive from amyloid PET-negative individuals using the Bio-Hermes cohort. After quality control and missing-data filtering, 988 participants and 295 proteins were analysed; 31 proteins showing group differences were used for supervised classification. Random Forest, Gradient Boosting, and Neural Network models were trained across four train/test splits with repeated cross-validation and class downsampling. Amyloid-positive and amyloid-negative groups differed across a subset of proteins, with five remaining significant after false discovery rate correction. Tree-based models performed most consistently, with Random Forest and Gradient Boosting achieving AUC values of 0.79–0.81 and balanced accuracy of 0.68–0.73. Eight proteins (SERPINA1, C3, CRP, APOE4, CFH, VTN, C1QTNF5, and PON1) emerged as recurring high-importance features. These findings indicate that discovery-driven plasma proteomics can identify multi-protein signatures associated with amyloid status and can complement established single-analyte blood biomarkers by adding pathway-level information. Full article

This prospective study evaluated first-trimester markers in pregnancies with isolated and combined forms of fetal growth disorders and gestational diabetes mellitus (GDM). Among 1869 screened women, the analysis included 83 controls, 55 GDM, 22 isolated intrauterine growth restriction (iIUGR), and 33 isolated large-for-gestational-age (iLGA) cases, with GDM subgroups stratified by fetal growth (GDM with normal fetal weight, GDM + IUGR, and GDM + LGA). First-trimester clinical and routine biochemical parameters were recorded, and serum concentrations of 80 proteins were measured using targeted LC-MRM-MS proteomics. Different trajectories emerged: IUGR phenotypes showed low PAPP-A/PlGF and high TSH (p < 0.01), indicating early placental insufficiency, while macrosomia showed opposite trends. GDM + IUGR represented the most severe “double hit” phenotype (lowest PlGF, earliest delivery), whereas GDM + LGA showed increased umbilical artery resistance despite excessive growth, suggesting endothelial dysfunction. Targeted proteomics revealed characteristic signatures: iIUGR featured low complement (C4A|C4B) and IGF proteins (IGFALS, IGFBP3) versus GDM and iLGA (p < 0.001); GDM + IUGR showed elevated PZP and CD5L versus iIUGR (p < 0.05); GDM + LGA was marked by high C4BPA and low RBP4, SERPINA7 versus iLGA (p < 0.05). Complement and IGF pathways were consistently implicated. Machine learning achieved 77% sensitivity for IUGR prediction using clinical parameters and 88% sensitivity for LGA prediction using proteomic data. These findings demonstrate that fetal growth disorders represent pathophysiologically unique entities detectable in the first trimester, enabling early risk stratification and personalized management. Full article

Background and Clinical Significance: Alpha-1 antitrypsin deficiency (AATD) is an autosomal codominant disorder caused by pathogenic variants in the SERPINA1 gene, resulting in reduced circulating alpha-1 antitrypsin (AAT) or production of dysfunctional protein. AAT is the principal inhibitor of neutrophil elastase, and its deficiency leads to unchecked proteolytic activity, progressive destruction of lung parenchyma, and increased susceptibility to infections. Severe deficiency, particularly in individuals homozygous for the Z allele (PI*ZZ), predisposes to early-onset panacinar emphysema, chronic airflow obstruction, and liver disease. Despite its clinical relevance, AATD remains markedly underdiagnosed and is frequently misclassified as smoking-related chronic obstructive pulmonary disease (COPD), delaying access to disease-modifying therapy, genetic counselling, and preventive strategies. Early recognition is therefore essential to improve outcomes. Case Presentation: We report the case of a 68-year-old ex-smoker with a long-standing diagnosis of “COPD” who presented with acute-on-chronic type 2 respiratory failure and community-acquired pneumonia. Spirometry revealed severe airflow obstruction, and high-resolution computed tomography demonstrated extensive basilar panlobular emphysema, raising suspicion for AATD. Serum AAT concentration was critically low at 26.8 mg·dL⁻¹, and isoelectric focusing confirmed a PI*ZZ phenotype. Next-generation sequencing identified homozygosity for the SERPINA1 c.1096G>A (Z) variant, with no additional pathogenic alleles. Cascade family screening revealed multiple heterozygous PI*MZ relatives. Before augmentation therapy could be initiated, the patient developed severe Legionella pneumophila pneumonia with secondary bacterial superinfection, progressing to refractory septic shock and death. Conclusions: This case illustrates how AATD can masquerade as smoking-related COPD for years, leading to missed opportunities for timely intervention. It underscores the importance of testing all adults with COPD or refractory asthma at least once, regardless of age or smoking history. Early diagnosis enables initiation of augmentation therapy, targeted vaccination, lifestyle modification, and genetic counselling, ultimately improving prognosis and reducing preventable morbidity and mortality. Full article

Background/Objectives: Currently available treatments approved by the Food and Drug Administration for Alzheimer’s disease (AD) either only target the symptoms of AD or, if disease-modifying, have severe side effects. This study aims to explore the potential of the FDA-approved Rho-associated kinase (ROCK) inhibitor netarsudil to reduce tau, a pathological protein in AD. Methods: We explored the pharmacokinetic and pharmacodynamic properties of netarsudil following a single intraperitoneal (i.p.) injection in wild-type mice. The efficacy of netarsudil was assessed using ELISA targeting tau/phosphorylated tau (ptau), as well as mass spectrometry-based proteomics. Results: We found that netarsudil is brain permeable, reaches peak concentrations rapidly and has moderate but sustained exposure in the central nervous system (CNS). Additionally, there was a statistically significant negative association between brain netarsudil exposure and tau and phosphorylated tau at residue 181 (ptau181). The exploratory proteomic analysis of mouse brains exposed to netarsudil revealed changes in mitochondrial function, enrichment of metallothioneins Mt1 and Mt2, and suppression of the AD-related genes Pzp and Serpina3m. Conclusions: The apparent reduction in AD pathological protein tau/ptau and a neuroprotective proteomic profile in vivo suggest the potential for netarsudil to be developed as a new AD therapeutic agent. Full article

Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder characterized by reduced circulating levels and/or impaired function of alpha-1 antitrypsin (AAT), a key serine protease inhibitor, in which loss of effective antiprotease protection results in unchecked neutrophil elastase activity and progressive lung tissue destruction. Although AATD accounts for approximately 1% of chronic obstructive pulmonary disease (COPD) cases and up to 2% of emphysema, AATD-related COPD remains largely underdiagnosed, despite guideline recommendations for systematic evaluation in patients with COPD, particularly in high-risk clinical settings. Pathologically, AATD-related COPD is not limited to the typical early-onset, lower-lobe-predominant emphysema, also including upper-lobe or mixed emphysema patterns, airway-predominant disease, small airways dysfunction, and bronchiectasis. Clinically, AATD-related COPD is distinguished from smoking-related COPD by its earlier onset, physiological impairment that is often disproportionate to smoking exposure, and its potential presence of certain extrapulmonary manifestations. Diagnosis and monitoring are also challenged by the frequent discordance between airflow limitation and gas transfer impairment, as well as the early involvement of small airways, limiting reliance on spirometry alone. A multimodal assessment incorporating more sensitive functional techniques and CT densitometry may provide a more precise evaluation of disease burden, progression, and prognosis. Management generally follows standard COPD principles, with intravenous AAT augmentation therapy remaining currently the only established disease-modifying therapy for selected patients with severe deficiency. The advent of new pharmacological and gene-based therapies emphasizes the importance of developing personalized management strategies that integrate genotype and longitudinal disease behavior. This narrative review summarizes current evidence on AATD-associated COPD, focusing on its genetic basis and pathophysiological features, clinical and functional heterogeneity, current and emerging diagnostic and monitoring approaches, and disease-specific management considerations. Full article

Background: Oral Submucous Fibrosis (OSMF) is a significant global oral health problem, particularly prevalent in India, with a high risk of progression to Oral Squamous Cell Carcinoma (OSCC). This study investigates the molecular mechanisms involved in the transformation of OSMF to OSCC using transcriptomic profiling. Methods: High-throughput RNA sequencing was performed on fresh de novo OSCC samples (n = 8) and OSMF derived OSCC using Illumina-compatible NEXTflex Rapid Directional RNA Sequencing. Normalization and differential gene expression analysis were conducted, and genes exhibiting an absolute log2 fold change of ≥2 with a co-variate-adjusted p-value ≤ 0.05 were identified as significant. Results: Upregulated genes were associated with cytokine and immune responses (ABRA, TTTY14, EIF1AY), cellular proliferation and apoptosis (LINC00314, RPS4Y1, SERPINA5, TRIM63, FABP7), and energy metabolism, indicating metabolic adaptations during malignant progression. Pathway analysis showed increased expression of TNNT1, TNNI1, MYL4, and ACTN3, implicating muscle development and embryonic pathways in OSMF transformation. Conversely, genes related to epithelial differentiation and keratinization (FLG, FLG2, HRNR, TCHH, KRT73), immune regulation and tumor suppression (HLA-G, UNC5D), and metabolic signaling were downregulated, reflecting loss of tissue integrity and immune control. Conclusions: OSMF-derived OSCC exhibits a distinct transcriptomic landscape compared with de novo OSCC, characterized by altered epithelial differentiation, immune modulation, and activation of developmental pathways. The observed gene dysregulation findings establish that OSCC developing in the background of OSMF is molecularly distinct from de novo OSCC, underscoring the biological impact of the pre-existing fibrotic milieu on tumor transcriptional architecture. Full article

Background/Objectives: Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder classically associated with emphysema and COPD. However, emerging evidence indicates that its clinical spectrum extends to airway-predominant diseases such as bronchiectasis and asthma, where protease–antiprotease imbalance and neutrophilic inflammation may drive tissue injury. This narrative review aims to synthesize current evidence on the relationship between AATD and airway diseases beyond emphysema, focusing on epidemiological patterns, underlying mechanisms, diagnostic strategies, and therapeutic implications. Methods: A narrative synthesis of the literature was performed, integrating data from registries, with observational and translational studies addressing the prevalence, pathobiology, and therapeutic implications of AATD in bronchiectasis, asthma, and severe asthma. Epidemiologic and mechanistic insights were analyzed to identify overlapping pathways and evidence gaps. Results: Evidence supports a non-negligible prevalence of bronchiectasis and asthma among AATD individuals, particularly in severe or heterozygous genotypes. Neutrophil elastase overactivity, impaired mucociliary clearance, and chronic neutrophilic inflammation emerge as shared mechanisms promoting bronchial remodeling and airflow limitation. In asthma, AATD appears linked to T2-low, steroid-resistant phenotypes and persistent obstruction, whereas in severe asthma cohorts, up to 20% may carry non-PiMM SERPINA 1 variants. No randomized trials have evaluated augmentation therapy and standardized screening algorithms are lacking. Conclusions: AATD represents a systemic disorder with clinically relevant airway manifestations beyond COPD and emphysema. Targeted testing should be considered in patients with idiopathic bronchiectasis or severe asthma. Future genotype-stratified, prospective studies are required to clarify causality, define biomarkers of disease activity, and evaluate the potential role of anti-protease-based therapeutic strategies. Full article

Background: Rheumatoid arthritis (RA) is a systemic, pro-inflammatory, autoimmune disease that mainly affects the joints in a symmetrical manner. Differential proteomic profiling through Sequential Window Acquisition of all Theoretical Fragment Ion Mass Spectra (SWATH-MS/MS) helps in a better understanding of the RA pathogenesis. In this study, we compared the differentially upregulated proteins with those associated with fibrosis to gain a deeper understanding of the fibrotic aspect of RA. Methods: We analyzed plasma proteomics data, previously obtained by SWATH-MS/MS. Our focus was on proteins associated with Leucine Rich Alpha2glycoprotein1 (LRG1) and we employed an in silico method. Results: We identified common proteins between RA and fibrosis. Among them, LRG1 and Serine Protease Inhibitor Clade A, Member 1 (SERPINA1) showed a high co-expression score in the gene clusters. LRG1 is both pro-inflammatory and pro-fibrotic, while SERPINA1 is an anti-inflammatory protein that inhibits pro-inflammatory and pro-fibrotic molecules (Elastase). Further, docking studies and a simulation study of the docked complexes with the analysis of Hydrogen bonds, Solvent Accessible Surface Area (SASA), Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF) and Radius of gyration (Rg), suggested a strong interaction between the two partners, LRG1 and SERPINA1. Conclusions: Our study suggests that LRG1 may inhibit SERPINA1 and promote inflammation and fibrotic processes by disrupting SERPINA1’s primary function. Full article

Background/Objectives: Male infertility, including primary and secondary infertility, is significantly influenced by oxidative stress, which disrupts sperm function and fertility. Seminal plasma, a protein-rich fluid essential for sperm protection and function, represents a valuable source for identifying biomarkers through proteomic analysis. While previous studies have explored seminal plasma proteins in fertility, the specific proteomic changes associated with oxidative stress in secondary infertility remain unclear. This study aimed to characterize these alterations by analyzing seminal plasma from three groups: men with secondary infertility, fertile donors with high oxidative stress, and fertile donors without oxidative stress. Methods: Pooled semen samples from each group underwent quantitative proteomics analysis using advanced mass spectrometry, with subsequent bioinformatic analysis using tools like DAVID, STRING, and IPA for identifying differentially expressed proteins (DEPs). Results: Quantitative proteomic analysis identified 377 DEPs in secondary infertility and 523 DEPs in fertile donors with high oxidative stress compared to controls. Bioinformatic analysis revealed seven shared pathways, including acute-phase response signaling, organismal injury, cellular movement, cell-to-cell signaling, free radical scavenging, immune cell trafficking, and Hematological system development. Notably, C3 and SERPINA3 exhibited significant alterations, along with proteins involved in sperm motility, capacitation, and fertilization, suggesting their potential roles in impaired fertility. Conclusions: These findings underscore the link between oxidative stress and secondary infertility and highlight specific seminal plasma proteins as potential biomarkers and therapeutic targets for diagnosing and treating male infertility. Full article

Neuroinflammation plays a dual role in brain health supporting defense and repair, but causes neurotoxicity when persistent. Microglia and astrocytes coordinate these responses through cytokine signaling and extracellular vesicles (EVs), though their vesicle-mediated communication remains unclear. This study investigated whether EVs from activated microglia (ABEVs) influence astrocyte polarization and inflammatory signaling. BV-2 microglial cells were activated with lipopolysaccharide (LPS), and microvesicle (ABMVs) and exosome (ABEXs) EVs were isolated via sequential ultracentrifugation. Primary mouse astrocytes were treated with LPS, ABMVs, or ABEXs, and expression of reactive astrocyte markers (C3, Serpina3n, S100a10, Sphk1) and inflammatory mediators (Lcn2, Il-1β, Ccl2, Ccl5, Cxcl10) was quantified, and EV protein cargo was analyzed by mass spectrometry and proteomics. LPS-treated astrocytes exhibited increased C3 and Serpina3n and decreased S100a10, consistent with reactive polarization. ABEXs mimicked this effect, significantly inducing C3, Serpina3n, and Sphk1, whereas ABMVs had a weaker influence. ABEXs also upregulated Lcn2 and Il-1β, partially reproducing microglial inflammatory effects. Proteomic profiling revealed marked cargo differences: ABEXs exhibited 16 upregulated proteins linked to NOD-like receptor signaling compared to non-activated BEXs, and 165 proteins associated with ribosome biogenesis and spliceosome pathways compared to ABMVs, indicating subtype-specific signaling potential. Collectively, our findings demonstrate that microglia-derived EVs modulate astrocytic polarization and cytokine profiles in a cargo-dependent manner, emphasizing their importance in interglial communication and revealing novel targets for neuroinflammatory modulation. Full article

Bronchopulmonary dysplasia (BPD) is a chronic lung condition in preterm infants characterized by impaired alveolar development, disrupted vascular growth, and persistent inflammation. These alterations, which often arise from early exposure to mechanical ventilation, oxygen toxicity, and infection, can lead to long-term structural and functional deficits in the developing lung. In adulthood, chronic obstructive pulmonary disease (COPD) represents a major cause of morbidity and mortality and is defined by progressive airflow obstruction, reduced respiratory capacity, and chronic inflammatory responses. Although traditionally considered a disease of adult smokers, growing evidence suggests that early-life respiratory insults play a key role in shaping long-term lung health. Recent studies reveal a biologically plausible link between BPD and later COPD, indicating that premature birth, impaired lung growth, and early inflammatory injury may predispose individuals to earlier or more severe COPD development. This review explores the shared molecular pathways connecting these conditions, focusing on overlapping inflammatory biomarkers such as IL1B, IL6, IL8, TNF, TGFB, and VEGF, which collectively reflect persistent dysregulation of immune and repair mechanisms. Additionally, common genetic variants, including SERPINA1 and HHIP, may contribute to susceptibility across the lifespan. Emerging biomarkers—such as PRMT7, cathelicidin/LL-37, CRISPLD2, and GDF15—offer further insight into disease progression. Identifying these shared markers may ultimately improve early detection and help clinicians pinpoint infants with BPD who face an elevated risk of developing COPD later in life. Full article

Background/Objectives: Doxorubicin (DOX) is an effective chemotherapeutic agent whose clinical utility is limited by cardiotoxicity. To investigate underlying mechanisms, we employed a multi-omics approach integrating transcriptomics and proteomics, leveraging established mouse models of chronic DOX-induced cardiotoxicity. Methods: Five-week-old male mice received weekly DOX (4 mg/kg) or saline injections for six weeks, with heart tissues harvested 4 days post-treatment. Differentially expressed genes (DEGs) and proteins (DEPs) were identified by bulk RNA-seq and proteomics, validated via qPCR and Western blot, respectively. Key DEPs were validated in plasma samples from DOX-treated breast cancer patients. Additionally, temporal comparison was conducted between DEPs in the mice hearts 4 days and 6 weeks post-DOX. Results: RNA-seq revealed upregulation of stress-responsive genes (Phlda3, Trp53inp1) and circadian regulators (Nr1d1), with downregulation of Apelin and Cd74. Proteomics identified upregulation of serpina3n, thrombospondin-1, and epoxide hydrolase 1. Plasma SERPINA3 concentrations were significantly elevated in breast cancer patients 24 h post-DOX. Gene set enrichment analysis (GSEA) revealed upregulated pathways, including p53 signaling, apoptosis, and unfolded protein response. Integrated omics analysis revealed 2089 gene–protein pairs. GSEA of concordant gene–protein pairs implicated p53 signaling, apoptosis, and epithelial–mesenchymal transition in upregulated pathways, while oxidative phosphorylation and metabolic pathways were downregulated. Temporal comparison with a delayed timepoint (6 weeks post-DOX) uncovered dynamic remodeling of cardiac signaling, with early response dominated by inflammatory and apoptotic responses, and delayed response marked by cell cycle and DNA repair pathway activation. Conclusions: This integrated omics study reveals key molecular pathways and temporal changes in DOX-induced cardiotoxicity, identifying potential biomarkers for future cardioprotective strategies. Full article

Alpha-1 antitrypsin (AAT) is a serine protease inhibitor with potent anti-inflammatory and immunomodulatory properties, but its role in cancer is context-dependent across tumor types. We integrated transcriptomic analyses of human melanoma cohorts, in vivo studies using AAT-transgenic (hAAT-TG) mice, and in vitro assays in murine and human melanoma cells to define the biological functions of AAT in melanoma. SERPINA1 expression increased progressively from normal skin to nevi and metastatic melanoma, yet higher intratumoral levels correlated with improved overall survival in metastatic disease. In hAAT-TG mice, melanoma growth was markedly inhibited compared with wild-type controls, and the inhibitory effect required CD8⁺ T cells and was enhanced by CD4⁺ T-cell depletion, demonstrating that AAT promotes cytotoxic T-cell activity while attenuating regulatory T-cell suppression. Histologic analysis showed heavily pigmented tumors in hAAT-TG mice. In vitro, hAAT upregulated melanocytic differentiation markers (MITF, TYR, PMEL, MART-1) and increased melanin production in murine and human melanoma lines, suggesting enhanced tumor immunogenicity. In conclusion, hAAT exerts antitumor effects in melanoma indirectly by reprogramming the tumor microenvironment toward differentiation and immune activation. These findings highlight a previously unrecognized role for AAT as a dual immunoregulatory and differentiation-promoting factor and support AAT as a potential immunoregulatory adjuvant in melanoma. Full article