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Potentiation of neutrophil extracellular trap (NET) release is one mechanism by which antiphospholipid antibodies (aPL Abs) effect thrombotic events in patients with antiphospholipid syndrome (APS). Surface adenosine receptors trigger cyclic AMP (cAMP) formation in neutrophils, and this mechanism has been proposed to regulate NETosis in some contexts. Here we report that selective agonism of the adenosine A 2A receptor (CGS21680) suppresses aPL Ab-mediated NETosis in protein kinase A-dependent fashion. CGS21680 also reduces thrombosis in the inferior vena cavae of both control mice and mice administered aPL Abs. The antithrombotic medication dipyridamole is known to potentiate adenosine signaling by increasing extracellular concentrations of adenosine and interfering with the breakdown of cAMP. Like CGS21680, dipyridamole suppresses aPL Ab-mediated NETosis via the adenosine A 2A receptor and mitigates venous thrombosis in mice. In summary, these data suggest an anti-inflammatory therapeutic paradigm in APS, which may extend to thrombotic disease in the general population. Antiphospholipid syndrome is characterised by increased neutrophil extracellular trap formation (NETosis) and, consequently, increased thrombotic events. Here Ali et al. show that treatment with adenosine receptor agonists suppresses NETosis and venous thrombosis in mouse models of antiphospholipid syndrome.

Objectives Neutrophils and neutrophil extracellular traps (NETs) contribute to the vascular complications of multiple diseases, but their role in systemic sclerosis (SSc) is understudied. We sought to test the hypothesis that NETs are implicated in SSc vasculopathy and that treatment with prostacyclin analogs may ameliorate SSc vasculopathy not only through vasodilation but also by inhibiting NET release. Methods Blood from 125 patients with SSc (87 diffuse cutaneous SSc and 38 limited cutaneous SSc) was collected at a single academic medical center. Vascular complications such as digital ulcers, pulmonary artery hypertension, and scleroderma renal crisis were recorded. The association between circulating NETs and vascular complications was determined using in vitro and ex vivo assays. The impact of the synthetic prostacyclin analog epoprostenol on NET release was determined. Results Neutrophil activation and NET release were elevated in patients with SSc-associated vascular complications compared to matched patients without vascular complications. Neutrophil activation and NETs positively correlated with soluble E-selectin and VCAM-1, circulating markers of vascular injury. Treatment of patients with digital ischemia with a synthetic prostacyclin analog boosted neutrophil cyclic AMP, which was associated with the blunting of NET release and reduced NETs in circulation. Conclusion Our study demonstrates an association between NETs and vascular complications in SSc. We also identified the potential for an additional therapeutic benefit of synthetic prostacyclin analogs, namely to reduce neutrophil hyperactivity and NET release in SSc patients. Key message • Neutrophils and NETs are understudied in the pathogenesis of SSc. • Plasma NETs are associated with SSc vascular complications and may identify patients deserving proactive treatments. • Prostacyclin analogs potentially protect against SSc vasculopathy-related NET release by boosting intracellular cyclic AMP.

Background Soluble CD13 (sCD13), generated through cleavage of membrane-bound CD13 by matrix metalloproteinase-14 (MMP14), exhibits proinflammatory, angiogenic, and arthritogenic properties. Its known receptors include bradykinin receptor B1 (B1R) and protease-activated receptor 4 (PAR4). Building on our previous findings that the sCD13-B1R axis contributes to fibrosis in systemic sclerosis (SSc), we investigated whether plasma sCD13 levels and gene expression by peripheral blood cells are associated with clinical features of SSc. Methods Plasma sCD13 levels were quantified by ELISA in SSc patients and healthy controls enrolled at the University of Michigan Scleroderma Program. Three independent patient cohorts were analyzed to assess associations with disease subtype, vascular complications, and early-stage disease. Public transcriptomic datasets were used to evaluate the expression of CD13-related genes in peripheral blood cells. Statistical analyses included t-tests, one-way ANOVA, chi-square tests, and correlation analyses, with significance defined as p  < 0.05. Results Plasma sCD13 levels were significantly elevated in SSc patients compared to healthy controls but showed no association with vascular complications or baseline severity of skin disease as shown by mRSS, interstitial lung disease, pulmonary function, and autoantibody profiles. In early-stage SSc, higher baseline sCD13 predicted greater improvement in skin fibrosis over one year ( r = -0.42, p  = 0.001), and longitudinal decline in sCD13 corelated with changes in DLCO% ( r  = 0.53, p  = 0.04). Transcriptomic analysis revealed upregulation of ANPEP (CD13), MMP14 , and F2RL3 (PAR4) in SSc blood, with strong positive correlations between ANPEP and both MMP14 and F2RL3 . In addition, ANPEP and MMP14 expression correlated with TGFB1 and IL6 , key cytokines in SSc pathogenesis. Single-cell data further localized ANPEP and MMP14 expression to myeloid cells, particularly CD14⁺ and CD16⁺ monocytes and dendritic cells. Conclusions Our results demonstrate that circulating sCD13 reflects dynamic disease activity rather than static severity in SSc. Its expression in myeloid cells and linkage to fibrotic cytokines suggest an active role in disease pathogenesis. While systemic sCD13 alone may have limited biomarker utility, longitudinal monitoring and integration with tissue-level markers could enhance prediction of disease trajectory and therapeutic response.

BackgroundLiver and breast cancers are among the leading causes of cancer-related deaths worldwide, prompting researchers to seek natural anticancer agents and reduce chemotherapy side effects. Red beetroot (Beta vulgaris Linnaeus), rich in polyphenols and powerful antioxidants, has shown potential in cancer prevention. This study aimed to evaluate the impact of red beetroot-derived anthocyanin (Ant), Ant-loaded chitosan nanoparticles (Ant NPs), cisplatin (Cis), Cis-loaded chitosan (Cis NPs), and Cis + Ant-loaded chitosan NPs on human hepatoma HepG2 and breast adenocarcinoma MCF7 cell lines.MethodsNPs preparation was evaluated by zeta potential, FTIR, and SEM. The cytotoxic, apoptotic, antioxidant, anti-inflammatory, anti-metastatic, and anti-angiogenic effects were assessed by MTT assay, qPCR, AO/EB staining, and flow cytometry.ResultsTreatment with Ant, Ant NPs, Cis, Cis NPs, and Cis + Ant NPs caused cytotoxicity in HepG2 and MCF7 with best effect in Cis-treated cells. The anticancer effects were attributed to mitochondrial-dependent apoptosis (with high Bax and low Bcl2 expression), chromatin disintegration, and cell cycle arrest in G2/M and S phases. All treatments inhibited migration by downregulating the migration-related gene MMP9 and upregulating the anti-migratory gene TIMP1 and decreased the angiogenesis-related gene VEGF and the inflammatory gene TNFα with best results in Cis NPs-treated cells. Interestingly, Ant, Ant NPs, and Cis + Ant NPs increased the antioxidant status (high GSH and upregulated expression of Nrf2 and OH-1) and decreased drug resistance-related MAPK1 and MDR1 genes compared to Cis and Cis NPs-treated cells.ConclusionsAnthocyanin and cisplatin-loaded chitosan nanoparticles effectively combat breast and liver cancers by inducing cancer cell apoptosis, enhancing antioxidant defenses, and reducing inflammation. They also inhibit tumor spread and blood vessel formation through downregulation of MMP9 and VEGF, highlighting their therapeutic potential.

Ehrlich ascites carcinoma (EAC), a rapidly growing tumor model, poses challenges in chemotherapy due to toxicity and resistance. Liposomal drug delivery improves anticancer therapy by enhancing bioavailability, targeting, and reducing systemic toxicity. Cisplatin (Cis), although effective, induces severe hepatic and renal toxicity. Anthocyanins (Ant), natural flavonoids with antioxidant and anticancer activities, can synergize with chemotherapy and reduce toxicity. This study evaluated three nano-liposomal formulations for EAC: Ant-loaded liposomes (Ant Ls), Cis-loaded liposomes (Cis Ls), and their combination (Cis + Ant Ls). Nano-liposomes containing Cis and/or Ant were prepared by thin-film hydration, functionalized with folic acid for targeting, and characterized by TEM for size and morphology. Encapsulation efficiency and drug release (48 h, dialysis) were determined. Cytotoxicity was tested on HCT 116 and Vero cells (MTT assay). Serum biochemical markers (ALT, AST, urea, and creatinine) were quantified, while tumor tissues were analyzed for apoptotic (caspase-3, Bcl2), inflammatory (IL1β), angiogenic (VEGF), metastatic (MMP9), and antioxidant (Nrf2, HO-1) genes using qPCR. Ant Ls demonstrated a high encapsulation efficiency of 93.06% and exhibited sustained release profiles, achieving the highest cumulative drug release of 59.11% at 48 h. Cis Ls and/or Ant Ls demonstrated significant cytotoxic (P < 0.05) effects on HCT 116 colon cancer cells while exhibiting minimal toxicity to normal Vero cells. In comparison to untreated EAC controls, mice treated with Cis Ls and/or Ant Ls exhibited significantly (P < 0.05) enhanced liver and renal function and structure, as evidenced by reductions in ALT, AST, urea, and creatinine and histopathology lesions. The treatments also decreased EAC burden as noticed by a reduction in total and viable tumor cell counts, and ascitic fluid volume, along with an increase in non-viable cells. The anticancer effect of Cis Ls and/or Ant Ls was attributed to multiple mechanisms, including increased apoptosis, reduced inflammation, inhibited angiogenesis, and suppression of metastasis. The combined treatment enhanced antioxidant defenses to mitigate Cis toxicity. The combination of Cis Ls and Ant Ls markedly decreased tumor burden and demonstrated therapeutic synergy, suggesting potential for improved outcomes. Cis Ls and Ant Ls delivery strategy mitigates liver and kidney damage while enhancing anticancer efficacy against EAC.

CD39 and CD73 are surface enzymes that jut into the extracellular space where they mediate the step-wise phosphohydrolysis of the autocrine and paracrine danger signals ATP and ADP into anti-inflammatory adenosine. Given the role of vascular and immune cells' \"purinergic halo\" in maintaining homeostasis, we hypothesized that the ectonucleotidases CD39 and CD73 might play a protective role in lupus. Lupus was modeled by intraperitoneal administration of pristane to three groups of mice: wild-type (WT), CD39 , and CD73 . After 36 weeks, autoantibodies, endothelial function, kidney disease, splenocyte activation/polarization, and neutrophil activation were characterized. As compared with WT mice, CD39 mice developed exaggerated splenomegaly in response to pristane, while both groups of ectonucleotidase-deficient mice demonstrated heightened anti-ribonucleoprotein production. The administration of pristane to WT mice triggered only subtle dysfunction of the arterial endothelium; however, both CD39 and CD73 mice demonstrated striking endothelial dysfunction following induction of lupus, which could be reversed by superoxide dismutase. Activated B cells and plasma cells were expanded in CD73 mice, while deficiency of either ectonucleotidase led to expansion of T 17 cells. CD39 and CD73 mice demonstrated exaggerated neutrophil extracellular trap release, while CD73 mice additionally had higher levels of plasma cell-free DNA. These data are the first to link ectonucleotidases with lupus autoimmunity and vascular disease. New therapeutic strategies may harness purinergic nucleotide dissipation or signaling to limit the damage inflicted upon organs and blood vessels by lupus.

Ginger is known to have antiinflammatory and antioxidative effects and has traditionally been used as an herbal supplement in the treatment of various chronic diseases. Here, we report antineutrophil properties of 6-gingerol, the most abundant bioactive compound of ginger root, in models of lupus and antiphospholipid syndrome (APS). Specifically, we demonstrate that 6-gingerol attenuates neutrophil extracellular trap (NET) release in response to lupus- and APS-relevant stimuli through a mechanism that is at least partially dependent on inhibition of phosphodiesterases. At the same time, administration of 6-gingerol to mice reduces NET release in various models of lupus and APS, while also improving other disease-relevant endpoints, such as autoantibody formation and large-vein thrombosis. In summary, this study is the first to our knowledge to demonstrate a protective role for ginger-derived compounds in the context of lupus. Importantly, it provides a potential mechanism for these effects via phosphodiesterase inhibition and attenuation of neutrophil hyperactivity.

Anthocyanins are naturally occurring flavonoid chemicals that impart bright red, purple, and blue colors in several fruits, vegetables, and flowers. In addition to its visual attractiveness, anthocyanins provide several health advantages owing to their potent antioxidant, anti-inflammatory, and anticancer characteristics. This study examines several anthocyanin extraction methods, including solvent-based and environmentally friendly procedures, while emphasizing their benefits and drawbacks. Additionally, it explores current advancements in anthocyanin encapsulation methods that improve the stability, bioavailability, and controlled release of these beneficial molecules in food and medicinal applications. The molecular processes by which anthocyanins provide health benefits, including neuroprotection, cardiovascular health, the treatment of diabetes, and cancer prevention, are examined in depth. The issues related to anthocyanin degradation and their potential solutions are discussed, highlighting the need for further research to enhance the utilization of anthocyanins across various sectors. This study seeks to thoroughly analyze contemporary anthocyanin research, presenting insights into their potential as functional components in health-enhancing products.

Neutrophil-mediated activation and injury of the endothelium play roles in the pathogenesis of diverse disease states ranging from autoimmunity to cancer to COVID-19. Neutralization of cationic proteins (such as neutrophil extracellular trap–derived [NET-derived] histones) with polyanionic compounds has been suggested as a potential strategy for protecting the endothelium from such insults. Here, we report that the US Food and Drug Administration–approved polyanionic agent defibrotide (a pleiotropic mixture of oligonucleotides) directly engages histones and thereby blocks their pathological effects on endothelium. In vitro, defibrotide counteracted endothelial cell activation and pyroptosis-mediated cell death, whether triggered by purified NETs or recombinant histone H4. In vivo, defibrotide stabilized the endothelium and protected against histone-accelerated inferior vena cava thrombosis in mice. Mechanistically, defibrotide demonstrated direct and tight binding to histone H4 as detected by both electrophoretic mobility shift assay and surface plasmon resonance. Taken together, these data provide insights into the potential role of polyanionic compounds in protecting the endothelium from thromboinflammation with potential implications for myriad NET- and histone-accelerated disease states.

We previously reported that treatment of mice with 6-gingerol, the most abundant phytochemical in ginger root, leads to phosphodiesterase inhibition that counteracts neutrophil hyperactivity in models of antiphospholipid syndrome (APS) and lupus. Here, we explored the extent to which oral intake of a whole-ginger extract would similarly impact neutrophils in both autoimmune mice and healthy humans. In vitro, a solubilized ginger extract was able to attenuate neutrophil extracellular trap formation (NETosis) by human neutrophils through a mechanism that was dependent upon the cyclic AMP–dependent kinase, protein kinase A. When mice with features of either APS or lupus were administered a ginger extract orally, they demonstrated reduced circulating NETs, as well as the tempering of other disease outcomes, such as large-vein thrombosis (APS) and autoantibody production (lupus). In a pilot clinical trial, which was validated in a second cohort, daily intake of a ginger supplement for 7 days by healthy volunteers boosted neutrophil cAMP, inhibited NETosis in response to disease-relevant stimuli, and reduced circulating plasma NET levels. In summary, this work demonstrates that ginger intake restrains neutrophil hyperactivity in autoimmune mouse models and that ginger consumption by healthy individuals makes their neutrophils more resistant to NETosis.