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Hepatocellular carcinoma (HCC) is a highly lethal liver cancer with late diagnosis; therefore, the identification of new early biomarkers could help reduce mortality. We determine the tissue and plasma status of five annexins during hepatocarcinogenesis by diethylnitrosamine-induced cirrhosis-HCC. We found that Anxa5 was the earliest upregulated gene at week 12 after HCC initiation, while Anxa1 and Anxa2 were upregulated in advanced HCC stages (weeks 18 and 22). Furthermore, the protein level of Annexin A1, A2, A5 and A10 was increased from the early stages. Immunofluorescence and subcellular fractionation revealed Annexin A1, A2, and A5 in the cytoplasm and nuclei of tumor cells. Notably, increased plasma levels of Annexin A5 significantly (r 2  = 0.8203) correlated with Annexin A5 levels in liver tissue from week 12 and gradually increased until week 22. Using the TCGA database, we found that the expression of ANXA2 (HR = 1.7, p  = 0.0046) and ANXA5 (HR = 1.8, p  = 0.00077) was associated with poor survival in HCC patients. In conclusion, we have identified Annexin A1 and A5 as potentially useful early biomarkers for poor prognosis in HCC patients.

Antitumor immunity driven by intratumoral dendritic cells contributes to the efficacy of anthracycline-based chemotherapy in cancer. We identified a loss-of-function allele of the gene coding for formyl peptide receptor 1 (FPR1) that was associated with poor metastasis-free and overall survival in breast and colorectal cancer patients receiving adjuvant chemotherapy. The therapeutic effects of anthracyclines were abrogated in tumor-bearing Fpr1-/- mice due to impaired antitumor immunity. Fpr1-deficient dendritic cells failed to approach dying cancer cells and, as a result, could not elicit antitumor T cell immunity. Experiments performed in a microfluidic device confirmed that FPR1 and its ligand, annexin-1, promoted stable interactions between dying cancer cells and human or murine leukocytes. Altogether, these results highlight the importance of FPR1 in chemotherapy-induced anticancer immune responses.

Annexin A1 (ANXA1) has long been classed as an anti-inflammatory protein due to its control over leukocyte-mediated immune responses. However, it is now recognized that ANXA1 has widespread effects beyond the immune system with implications in maintaining the homeostatic environment within the entire body due to its ability to affect cellular signalling, hormonal secretion, foetal development, the aging process and development of disease. In this review, we aim to provide a global overview of the role of ANXA1 covering aspects of peripheral and central inflammation, immune repair and endocrine control with focus on the prognostic, diagnostic and therapeutic potential of the molecule in cancer, neurodegeneration and inflammatory-based disorders.

Annexin-1 (ANXA1) has shown neuroprotective effects and microglia play significant roles during central nervous system injury, yet the underlying mechanisms remain unclear. This study sought to determine whether ANXA1 regulates microglial response to oxygen–glucose deprivation/reperfusion (OGD/R) treatment and to clarify the downstream molecular mechanism. In rat hippocampal slices, OGD/R treatment enhanced the ANXA1 expression in neuron, the formyl peptide receptor (FPRs) expression in microglia, and the microglial activation in the CA1 region (cornu ammonis 1). These effects were reversed by the FPRs antagonist Boc1. The cell membrane currents amplitude of BV-2 microglia (the microglial like cell-line) was increased when treated with Ac2-26, the N-terminal peptide of ANXA1. Ac2-26 treatment enhanced BV-2 microglial migration whereas Boc1 treatment inhibited the migration. In BV-2 microglia, both the expression of the CK2 target phosphorylated α-E-catenin and the binding of casein kinase II (CK2) with α-E-catenin were elevated by Ac2-26, these effects were counteracted by the CK2 inhibitor TBB and small interfering (si) RNA directed against transcripts of CK2 and FPRs. Moreover, both TBB and siRNA-mediated inhibition of CK2 blocked Ac2-26-mediated BV-2 microglia migration. Our findings indicate that ANXA1 promotes microglial activation and migration during OGD/R via FPRs, and CK2 target α-E-catenin phosphorylation is involved in this process.

Recent studies indicate that microglial activation and the resulting inflammatory response could be potential targets of adjuvant therapy for ischemic stroke. Many studies have emphasized a well-established function of Annexin-A1 (ANXA1) in the immune system, including the regulation of microglial activation. Nevertheless, few therapeutic interventions targeting ANXA1 in microglia for ischemic stroke have been conducted. In the present study, Tat-NTS, a small peptide developed to prevent ANXA1 from entering the nucleus, was utilized. We discovered the underlying mechanism that Tat-NTS peptide targets microglial ANXA1 to protect against ischemic brain injury. Preclinical studies of ischemic stroke were performed using an oxygen-glucose deprivation and reperfusion (OGD/R) cell model in vitro and the middle cerebral artery occlusion (MCAO) animal model of ischemic stroke in vivo. Confocal imaging and 3D reconstruction analyses for detecting the protein expression and subcellular localization of microglia in vivo. Co-immunoprecipitation (Co-IP), immunoblotting, ELISA, quantitative real-time PCR (qRT-PCR), Luciferase reporter assay for determining the precise molecular mechanism. Measurement on the cytotoxicity of Tat-NTS peptide for microglia was assessed by CCK-8 and LDH assay. TUNEL staining was used to detect the microglia conditioned medium-mediated neuronal apoptosis. Adeno-associated viruses (AAVs) were injected into the cerebral cortex, striatum and hippocampal CA1 region of adult male Cx3cr1-Cre mice, to further verify the neurofunctional outcome and mechanism of Tat-NTS peptide by TTC staining, the modified Neurological Severity Score (mNSS) test, the open field test (OFT), the novel object recognition task (NORT), the Morris water maze (MWM) test, the long-term potentiation (LTP) and the Transmission electron microscopy (TEM). It was observed that administration of Tat-NTS led to a shift of subcellular localization of ANXA1 in microglia from the nucleus to the cytoplasm in response to ischemic injury. Notably, this shift was accompanied by an increase in ANXA1 SUMOylation in microglia and a transformation of microglia towards an anti-inflammatory phenotype. We confirmed that Tat-NTS-induced ANXA1 SUMOylation in microglia mediated IKKα degradation via NBR1-dependent selective autophagy, then blocking the activation of the NF-κB pathway. As a result, the expression and release of the pro-inflammatory factors IL-1β and TNF-α were reduced in both in vitro and in vivo experiments. Furthermore, we found that Tat-NTS peptide's protective effect on microglia relieved ischemic neuron apoptosis. Finally, we demonstrated that Tat-NTS peptide administration, through induction of ANXA1 SUMOylation in microglia, reduced infarct volume, improved neurological function and facilitated behavioral recovery in MCAO mice. Our study provides evidence for a novel mechanism of Tat-NTS peptide in regulating microglial ANXA1 function and its substantial neuroprotective effect on neurons with ischemic injuries. These findings suggest that Tat-NTS peptides have a high potential for clinical application and may be a promising therapeutic candidate for treating cerebral ischemia.

Background Microglia-induced excessive neuroinflammation plays a crucial role in the pathophysiology of multiple neurological diseases, such as ischaemic stroke. Controlling inflammatory responses is considered a promising therapeutic approach. Sirtuin 5 (SIRT5) mediates lysine desuccinylation, which is involved in various critical biological processes, but its role in ischaemic stroke remains poorly understood. This research systematically explored the function and potential mechanism of SIRT5 in microglia-induced neuroinflammation in ischaemic stroke. Methods Mice subjected to middle cerebral artery occlusion were established as the animal model, and primary cultured microglia treated with oxygen–glucose deprivation and reperfusion were established as the cell model of ischaemic stroke. SIRT5 short hairpin RNA, adenovirus and adeno-associated virus techniques were employed to modulate SIRT5 expression in microglia both in vitro and in vivo. Coimmunoprecipitation, western blot and quantitative real-time PCR assays were performed to reveal the molecular mechanism. Results In the current study, we showed that SIRT5 expression in microglia was increased in the early phase of ischaemic stroke. SIRT5 interacts with and desuccinylates Annexin A1 (ANXA1) at K166, which in turn decreases its SUMOylation level. Notably, the desuccinylation of ANXA1 blocks its membrane recruitment and extracellular secretion, resulting in the hyperactivation of microglia and excessive expression of proinflammatory cytokines and chemokines, ultimately leading to neuronal cell damage after ischaemic stroke. Further investigation showed that microglia-specific forced overexpression of SIRT5 worsened ischaemic brain injury, whereas downregulation of SIRT5 exhibited neuroprotective and cognitive-preserving effects against ischaemic brain injury, as proven by the decreased infarct area, reduced neurological deficit scores, and improved cognitive function. Conclusions Collectively, these data identify SIRT5 as a novel regulator of microglia-induced neuroinflammation and neuronal damage after cerebral ischaemia. Interventions targeting SIRT5 expression may represent a potential therapeutic target for ischaemic stroke.

Rheumatoid arthritis (RA) carries a twofold increased incidence of heart failure with preserved ejection fraction, accompanied by diastolic dysfunction, which can lead to death. The causes of diastolic dysfunction are unknown, and there are currently no well-characterized animal models for studying these mechanisms. Current medications for RA do not have marked beneficial cardio-protective effects. K/BxN F1 progeny and KRN control mice were analyzed over time for arthritis development, monitoring left ventricular diastolic and systolic function using echocardiography. Excised hearts were analyzed by flow cytometry, qPCR, and histology. In pharmacological experiments, K/BxN F1 mice were treated with human recombinant AnxA1 (hrAnxA1, 1 μg/mouse) or vehicle daily. K/BxN F1 mice exhibited fully developed arthritis with normal cardiac function at 4wk; however, byweek 8, all mice displayed left ventricular diastolic dysfunction with preserved ejection fraction. This dysfunction was associated with cardiac hypertrophy, myocardial inflammation and fibrosis, and inflammatory markers. Daily treatment of K/BxN F1 mice with hrAnxA1 from weeks 4 to 8 halted progression of the diastolic dysfunction. The treatment reduced cardiac transcripts of proinflammatory cytokines and profibrotic markers. At the cellular level, hrAnxA1 decreased activated T cells and increased MHC IIlow macrophage infiltration in K/BxN F1 hearts. Similar effects were obtained when hrAnxA1 was administered from week 8 to week 15. We describe an animal model of inflammatory arthritis that recapitulates the cardiomyopathy of RA. Treatment with hrAnxA1 after disease onset corrected the diastolic dysfunction through modulation of both fibroblast and inflammatory cell phenotype within the heart.

There is currently no therapy available for periprosthetic osteolysis, the most common cause of arthroplasty failure. Here, the role of AnxA1 in periprosthetic osteolysis and potential therapeutics were investigated. Reducing the expression of AnxA1 in calvarial tissue was found to be associated with increased osteolytic lesions and the osteolytic lesions induced by debris implantation were more severe in AnxA1-defecient mice than in wild-type mice. AnxA1 inhibits the differentiation of osteoclasts through suppressing NFκB signaling and promoting the PPAR-γ pathway. Administration of N-terminal-AnxA1 (Ac2-26 peptide) onto calvariae significantly reduced osteolytic lesions triggered by wear debris. These therapeutic effects were abrogated in mice that had received the PPAR-γ antagonist, suggesting that the AnxA1/PPAR-γ axis has an inhibitory role in osteolysis. The administration of Ac2–26 suppressed osteolysis induced by TNF-α and RANKL injections in mice. These findings indicate that AnxA1 is a potential therapeutic agent for the treatment of periprosthetic osteolysis. Periprosthetic osteolysis is a cause of arthroplasty failure without available therapies. Here the authors show that Annexin A1 (AnxA1) is involved in in periprosthetic osteolysis and exerts potential therapeutic effects through suppressing NFκB signaling and promoting the PPAR-γ pathway resulting in inhibition of inflammation and osteoclasts differentiation induced by wear debris.

Objective: Annexin-1 (ANXA1), a member of the annexin family, plays a role in the resolution of inflammation and the regulation of anti-inflammatory responses, while annexin-2 (ANXA2) is involved in the initiation of the inflammatory responses. The aim of this study was to determine the effects of annexin family (ANXA1 and ANXA2) in periodontal disease. Methods: Healthy participants (n:25) and stage III, grade B periodontitis (n:25) patients enrolled for this study. Clinical periodontal parameters and the periodontal inflamed surface area (PISA) levels were noted. Serum, saliva, and gingival crevicular fluid (GCF) samples were collected to measure the ANXA1, ANXA2 and IL-1β levels. Results: Salivary and serum concentrations of ANXA1 was significantly lower in the periodontitis group than in the control group (respectively, p  = 0.0177 and p = < 0.0001). Periodontitis patients demonstrated higher serum ANXA2 and IL-1β concentrations compared to controls (respectively, p  = 0.0002 and p  = 0.0017). As an inflammatory index; saliva, serum and GCF ANXA1/ANXA2 ratio were significantly lower in the periodontitis group compared to healthy controls. Conclusions: The data suggest that periodontitis is associated with a disruption of the balance between pro-inflammatory mechanisms (ANXA2 and IL-1beta) and inflammation resolution (ANXA1), in parallel with PISA levels. Clinical Trial Registration: ClinicalTrials.gov NCT06554756 (15/08/2024).

N-formyl peptide receptors (FPRs) are critical regulators of host defense in phagocytes and are also expressed in epithelia. FPR signaling and function have been extensively studied in phagocytes, yet their functional biology in epithelia is poorly understood. We describe a novel intestinal epithelial FPR signaling pathway that is activated by an endogenous FPR ligand, annexin A1 (ANXA1), and its cleavage product Ac2-26, which mediate activation of ROS by an epithelial NADPH oxidase, NOX1. We show that epithelial cell migration was regulated by this signaling cascade through oxidative inactivation of the regulatory phosphatases PTEN and PTP-PEST, with consequent activation of focal adhesion kinase (FAK) and paxillin. In vivo studies using intestinal epithelial specific Nox1(-/-IEC) and AnxA1(-/-) mice demonstrated defects in intestinal mucosal wound repair, while systemic administration of ANXA1 promoted wound recovery in a NOX1-dependent fashion. Additionally, increased ANXA1 expression was observed in the intestinal epithelium and infiltrating leukocytes in the mucosa of ulcerative colitis patients compared with normal intestinal mucosa. Our findings delineate a novel epithelial FPR1/NOX1-dependent redox signaling pathway that promotes mucosal wound repair.