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PubMed2026

Mechanistic characterization and inhibition of PAD4-dependent NETosis following experimental neonatal hypoxic-ischemic brain injury.

Neonatal hypoxia-ischemia (HI) remains a major global cause of neonatal morbidity and mortality. To develop effective therapeutic strategies, a deeper understanding of the acute inflammatory processes following HI is required. As the role of peripheral immune cell infiltration is poorly understood we used single nuclei RNA sequencing to investigate acute sequalae post-HI. This revealed a distinct neutrophil population characterized by increased expression of markers associated with neutrophil extracellular trap (NET) formation. The study evaluated the therapeutic potential of inhibiting NETosis formation using the peptidylarginine-deiminase-4 (PAD4) inhibitor Cl-amidine. We demonstrated that while oxygen-glucose deprivation (OGD) induces NET-formation and matrix-metalloproteinase-9 release in neutrophils, this is significantly reduced by the PAD4 inhibitor Cl-amidine. Second, in a co-culture model, inhibition of NETosis during OGD conditions improved neuronal survival. Third, Cl-amidine treatment reduced brain tissue loss and decreased expression levels of NETosis-related proteins 48 h post-HI in vivo. Moreover, behavioral testing performed six weeks after HI revealed improved motor function in the treatment group. This study highlights the detrimental role of neutrophil activation and NETosis in exacerbating brain injury following neonatal HI. Targeting NET formation in the acute phase after HI may represent a promising therapeutic approach to improve both immediate and long-term neurological outcomes.

Animals↗

PubMed2025

Proteomic insights into platelet dysregulation and pathogenic mechanisms of chronic thromboembolic pulmonary hypertension.

BACKGROUND: Undissolved thrombus blocks the pulmonary arteries in chronic thromboembolic pulmonary hypertension (CTEPH), a potentially fatal illness that raises pulmonary resistance, causes right heart failure, and even results in death. Although platelets are linked to vascular dysfunction and thrombus formation, it is yet unknown what precise proteome alterations and mechanistic roles they play in CTEPH. METHODS: We extracted platelet-rich plasma from peripheral blood and separated the plasma to obtain enriched platelet pellet (EPP). Quantitative proteomics was used to examine EPP from CTEPH patients and healthy controls using mass spectrometry. The relationship between protein levels and clinical markers of right heart function was examined. Platelet activity, morphology, and interactions with other blood components were evaluated using transmission electron microscopy, immunofluorescence, and flow cytometry. RESULTS: The proteomic investigation found that 179 proteins were differentially expressed in CTEPH patients. The analysis revealed that these proteins were involved in crucial processes such as complement and coagulation cascades, phagosome, and neutrophil extracellular trap (NET) formation. Elevated proteins, specifically NOX2, PAD4, ITGB2, and HMGB1, have been associated to platelet-neutrophil aggregates and NET formation. In addition, enhanced P-selectin expression in platelets and plasma confirmed greater platelet activation in CTEPH patients. Notably, PAD4 and NOX2 levels showed a substantial correlation with hemodynamic parameters and right heart dysfunction. MPO-DNA, a NET marker associated with P-selectin and ITGB2 expression, was discovered in higher concentrations in CTEPH patients' plasmas. CONCLUSION: Platelet aggregation and activation in CTEPH encourage the formation of NETs, which advances the disease and prolongs thrombus. Right heart insufficiency and hemodynamic markers had a strong correlation with PAD4 and NOX2 levels, indicating that these biomarkers may be employed to assess the severity and prognosis of CTEPH disease and offer a fresh approach to targeted treatment. The results highlight the need for additional study to elucidate platelet-mediated pathways and create therapies for CTEPH that target platelets.

Humans↗

PubMed2025

Phytocompounds of Honey mesquite (Prosopis glandulosa) and Lodhra (Symplocos racemosa) in the management of COVID-19 associated rheumatoid arthritis (CARA).

COVID-19 persists globally with profound social and economic consequences, and its complex interplay with other diseases makes it a syndemic. Rheumatoid arthritis (RA), a chronic autoimmune disorder, has shown increased incidence during the pandemic, with patients displaying higher susceptibility to COVID-19. This overlap prompted the hypothesis of 'COVID-19-associated rheumatoid arthritis (CARA)'. The present study explores phytocompounds with anti-inflammatory and immunomodulatory properties as potential CARA therapeutics. Compounds from Prosopis glandulosa and Symplocos racemosa, both used in traditional medicine, were evaluated through molecular docking and simulation studies. Six inflammatory targets relevant to RA and COVID-19 -interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), granulocyte-macrophage colony-stimulating factor (GM-CSF), human leukocyte antigen DR4 (HLA-DR4), signal transducer and activator of transcription 4 (STAT4), and peptidyl arginine deiminase 4 (PAD4) were selected. Among the tested ligands, salidroside showed the strongest binding affinity, with energies of - 8.20 kcal/mol (IL-6), - 7.67 kcal/mol (TNF-α), - 8.53 kcal/mol (GM-CSF), - 8.80 kcal/mol (HLA-DR4), - 8.18 kcal/mol (STAT4), and - 7.91 kcal/mol (PAD4), indicating stable interactions. These findings suggest salidroside could modulate key inflammatory pathways and potentially reduce cytokine storms in COVID-19 patients. Existing RA and COVID-19 treatments often cause immunosuppression, increasing vulnerability to opportunistic infections (Datta et al in J Biomol Struct Dyn 41(8):3281-3294, 2022). Immunomodulatory phytocompounds like salidroside may offer safer, targeted alternatives without compromising immune defenses. However, this study is based on in silico analyses, and warrants in vitro and in vivo validation. Nevertheless, present work may represent an important step towards novel therapeutic strategies for COVID-19 Associated Rheumatoid Arthritis (CARA).

COVID-19↗

PubMed2025

Genetic suppressors of the growth-immunity trade-off in the Arabidopsis salicylic acid-accumulating dmr6 dlo1 mutant.

Plants actively suppress growth and development upon activation of immunity. In turn, when pathogen attack has subsided, immune responses are suppressed again. Phytohormones play an important role in regulating this balance and the growth-immunity trade-off in general. The trade-off is evident in the Arabidopsis dmr6 dlo1 mutant, which accumulates the immune-activating phytohormone salicylic acid (SA) to high levels, resulting in high disease resistance but repression of growth. Little is known about the SA-induced growth trade-off mechanism. In this study, we performed a genetic suppressor screen on the dmr6 dlo1 double mutant to select mutants with reduced growth repression and identify suppressors of the SA-mediated trade-off. We identified 7 independent zund (giant) mutants, with restored growth but retained resistance to downy mildew. Through bulked segregant analysis and whole-genome sequencing (BSA-seq), we identified three mutant alleles of MED15a, an NPR1 allele, one ICS1/SID2 allele, and a PAD4 splice defect. Genetic complementation of mutants confirmed the roles of these genes in the SA-mediated growth-immunity trade-off. We discuss their application in tweaking SA signaling to optimize the balance between growth and immunity that is important when deploying immunity traits in breeding.

Arabidopsis↗

PubMed2025

Associations of PTPN22 and PADI4 polymorphisms with rheumatoid arthritis in ASWAN.

BACKGROUND: Rheumatoid Arthritis (RA) is a prevalent autoimmune disease affecting approximately 84,338 individuals in Egypt. Genetic predispositions, such as the PTPN22 and PADI4 genes, are linked to RA risk. PTPN22, a protein tyrosine phosphatase, a regulator of T-cell receptor signalling and PADI4, which is involved in citrullination, have shown varying levels of association with RA across populations. Studies have been inconclusive regarding their roles in RA susceptibility, progression, and activity. PATIENTS AND METHODS: A total of 240 participants were included in this study, RA patients and healthy controls from Aswan, Egypt. Genomic analysis was conducted to evaluate PTPN22 and PADI4 polymorphisms and their associations with RF and ACPA, Also, their correlation with disease activity markers, such as ESR, CRP, PGA and the Disease Activity Score (DAS28). RESULTS: No significant association between PTPN22 and RA with p value ≥ 0.05 with good matching regarding age and sex. However, PTPN22 significantly correlated with RF and ACPA, with p-value of 0.006 and < 0.001, respectively, suggesting its diagnostic value in RA. No significant associations were found between PTPN22 and disease activity markers such as the ESR and CRP. In contrast, PADI4 levels were elevated in the control groups with p value < 0.001 which is against the study hypothesis, which conflicts with findings from other studies. Despite this, PADI4 demonstrated greater specificity (73.3%), in RA diagnosis than did PTPN22 (45.3%), making it a potential diagnostic marker in combination with RF and ACPA. CONCLUSION: Our study revealed no significant associations between PTPN22 or PADI4 polymorphisms and RA susceptibility in the Aswan population. However, both genes were correlated with diagnostic markers such as RF and ACPA. The PADI4 has potential as a diagnostic marker with high specificity.

African↗