Explore the vast range of titles available.

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.

The blood–brain barrier (BBB), a critical guardian of communication between the periphery and the brain, is frequently compromised in neurological diseases such as multiple sclerosis (MS), resulting in the inappropriate passage of molecules and leukocytes into the brain. Here we show that the glucocorticoid anti-inflammatory messenger annexin A1 (ANXA1) is expressed in brain microvascular endothelial cells, where it regulates BBB integrity. In particular, ANXA1 ⁻/⁻ mice exhibit significantly increased BBB permeability as a result of disrupted interendothelial cell tight junctions, essentially related to changes in the actin cytoskeleton, which stabilizes tight and adherens junctions. This situation is reminiscent of early MS pathology, a relationship confirmed by our detection of a selective loss of ANXA1 in the plasma and cerebrovascular endothelium of patients with MS. Importantly, this loss is swiftly restored by i.v. administration of human recombinant ANXA1. Analysis in vitro confirms that treatment of cerebrovascular endothelial cells with recombinant ANXA1 restores cell polarity, cytoskeleton integrity, and paracellular permeability through inhibition of the small G protein RhoA. We thus propose ANXA1 as a critical physiological regulator of BBB integrity and suggest it may have utility in the treatment of MS, correcting BBB function and hence ameliorating disease.

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.

Neutrophils (also named polymorphonuclear leukocytes or PMN) are essential components of the immune system, rapidly recruited to sites of inflammation, providing the first line of defense against invading pathogens. Since neutrophils can also cause tissue damage, their fine-tuned regulation at the inflammatory site is required for proper resolution of inflammation. Annexin A1 (AnxA1), also known as lipocortin-1, is an endogenous glucocorticoid-regulated protein, which is able to counterregulate the inflammatory events restoring homeostasis. AnxA1 and its mimetic peptides inhibit neutrophil tissue accumulation by reducing leukocyte infiltration and activating neutrophil apoptosis. AnxA1 also promotes monocyte recruitment and clearance of apoptotic leukocytes by macrophages. More recently, some evidence has suggested the ability of AnxA1 to induce macrophage reprogramming toward a resolving phenotype, resulting in reduced production of proinflammatory cytokines and increased release of immunosuppressive and proresolving molecules. The combination of these mechanisms results in an effective resolution of inflammation, pointing to AnxA1 as a promising tool for the development of new therapeutic strategies to treat inflammatory diseases.

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.

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.

In this Opinion article, the effector function of annexin A1 in the anti-inflammatory action of glucocorticoids is discussed, and a model to address the opposing effects of glucocorticoids on the expression of annexin A1 by different immune cells is proposed. Glucocorticoids are widely used for the management of inflammatory diseases. Their clinical application stems from our understanding of the inhibitory effect of the corticosteroid hormone cortisol on several components of the immune system. Endogenous and exogenous glucocorticoids mediate their multiple anti-inflammatory effects through many effector molecules. In this Opinion article, we focus on the role of one such effector molecule, annexin A1, and summarize the recent studies that provide insight into its molecular and pharmacological functions in immune responses. In addition, we propose a model in which glucocorticoids regulate the expression and function of annexin A1 in opposing ways in innate and adaptive immune cells to mediate the resolution of inflammation.

Background Tyrosine kinase inhibitors (TKIs) such as sunitinib are multitarget antiangiogenic agents in clear cell renal cell carcinoma (ccRCC). They are widely used in the treatment of advanced/metastatic renal cancer. However, resistance to TKIs is common in the clinic, particularly after long-term treatment. YTHDC1 is the main nuclear reader protein that binds with m 6 A to regulate the splicing, export and stability of mRNA. However, the specific role and corresponding mechanism of YTHDC1 in renal cancer cells are still unclear. Methods The Cancer Genome Atlas (TCGA) dataset was used to study the expression of YTHDC1 in ccRCC. Cell counting kit-8 (CCK-8), wound healing, Transwell and xenograft assays were applied to explore the biological function of YTHDC1 in ccRCC. Western blot, quantitative real time PCR (RT‒qPCR), RNA immunoprecipitation PCR (RIP-qPCR), methylated RIP-qPCR (MeRIP-qPCR) and RNA sequencing (RNA-seq) analyses were applied to study the YY1/HDAC2/YTHDC1/ANXA1 axis in renal cancer cells. The CCK-8 assay and xenograft assay were used to study the role of YTHDC1 in determining the sensitivity of ccRCC to sunitinib. Results Our results demonstrated that YTHDC1 is downregulated in ccRCC tissues compared with normal tissues. Low expression of YTHDC1 is associated with a poor prognosis in patients with ccRCC. Subsequently, we showed that YTHDC1 inhibits the progression of renal cancer cells via downregulation of the ANXA1/MAPK pathways. Moreover, we also showed that the YTHDC1/ANXA1 axis modulates the sensitivity of tyrosine kinase inhibitors. We then revealed that HDAC2 inhibitors resensitize ccRCC to tyrosine kinase inhibitors through the YY1/HDAC2 complex. We have identified a novel YY1/HDAC2/YTHDC1/ANXA1 axis modulating the progression and chemosensitivity of ccRCC. Conclusion We identified a novel YY1/HDAC2/YTHDC1/ANXA1 axis modulating the progression and chemosensitivity of ccRCC.

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.

Renal cell carcinoma (RCC) is a malignant tumor of the kidneys. Approximately 70% of RCC cases are clear cell renal cell carcinoma with von Hippel–Lindau (VHL) gene mutation and activation of the vascular endothelial growth factor (VEGF) pathway. Tyrosine kinase inhibitors (TKIs) targeting VEGF have emerged as promising agents for RCC treatment. Apart from primary resistance, acquired resistance to TKIs after initial tumor regression is common in RCC. Recently, immune checkpoint inhibition, including PD‐1/PD‐L1 blockade, alone or in combination with TKIs has improved the overall survival of patients with RCC. Ribonucleotide reductase subunit M2 (RRM2) has been reported in many types of cancer and has been implicated in tumor progression. However, the role of RRM2 in TKIs resistance in RCC remains unclear. In this study, the authors have demonstrated that RRM2 is upregulated in sunitinib‐resistant RCC cells and patient tissues. They also find that RRM2 stabilizes ANXA1 and activates the AKT pathway independent of its ribonucleotide reductase activity, promoting sunitinib resistance in RCC. Moreover, RRM2 regulated antitumor immune responses, and knockdown of RRM2 enhance the anti‐tumor efficiency of PD‐1 blockade in renal cancer. Collectively, these results suggest that aberrantly expressed RRM2 may be a promising therapeutic target for RCC. RRM2 overexpression plays a key role in sunitinib resistance in patients with renal cell carcinoma and that RRM2 competes with UBE3A to prevent ANXA1 degradation. The up‐regulated ANXA1 activates AKT signaling pathway to regulate the sensitivity to sunitinib and PD‐1 blockade in renal cancer cells.