Annexin A1 Research Articles

ANXA2 is a potential biomarker for cancer prognosis and immune infiltration: A systematic pan-cancer analysis.

Background: Annexin A2 (ANXA2) belongs to the Annexin A family and plays a role in epithelial-mesenchymal transition, fibrinolysis, and other physiological processes. Annexin A2 has been extensively implicated in tumorigenesis and development in previous studies, but its precise role in pan-cancer remains largely unknown. Methods: We adopted bioinformatics methods to explore the oncogenic role of Annexin A2 using different databases, including the Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx) biobank, the Human Protein Atlas (HPA), the Gene Expression Profiling Interaction Analysis (GEPIA) and cBioPortal. We analyzed the differential expression of Annexin A2 in different tumors and its relationship with cancer prognosis, immune cell infiltration, DNA methylation, tumor mutation burden (TMB), microsatellite instability (MSI) and mismatch repair (MMR). Furtherly, we conducted a Gene Set Enrichment Analysis (GSEA) to identify the Annexin A2-related pathways. Results: Annexin A2 expression was upregulated in most cancers, except in kidney chromophobe (KICH) and prostate adenocarcinoma (PRAD). Annexin A2 showed a good diagnostic efficacy in twelve types of cancer. The high expression of Annexin A2 was significantly associated with a reduced overall survival, disease-specific survival and progression-free interval in seven cancers. The Annexin A2 expression was variably associated with infiltration of 24 types of immune cells in 32 tumor microenvironments. In addition, Annexin A2 expression was differently associated with 47 immune checkpoints, immunoregulators, DNA methylation, tumor mutation burden, microsatellite instability and mismatch repair in pan-cancer. Gene Set Enrichment Analysis revealed that Annexin A2 was significantly correlated with immune-related pathways in fifteen cancers. Conclusion: Annexin A2 widely correlates with immune infiltration and may function as a promising prognostic biomarker in many tumors, showing its potential as a target for immunotherapy in pan-cancer.

Annexin A1 is a polarity cue that directs mitotic spindle orientation during mammalian epithelial morphogenesis

Oriented cell divisions are critical for the formation and maintenance of structured epithelia. Proper mitotic spindle orientation relies on polarised anchoring of force generators to the cell cortex by the evolutionarily conserved protein complex formed by the Gαi subunit of heterotrimeric G proteins, the Leucine-Glycine-Asparagine repeat protein (LGN) and the nuclear mitotic apparatus protein. However, the polarity cues that control cortical patterning of this ternary complex remain largely unknown in mammalian epithelia. Here we identify the membrane-associated protein Annexin A1 (ANXA1) as an interactor of LGN in mammary epithelial cells. Annexin A1 acts independently of Gαi to instruct the accumulation of LGN and nuclear mitotic apparatus protein at the lateral cortex to ensure cortical anchoring of Dynein-Dynactin and astral microtubules and thereby planar alignment of the mitotic spindle. Loss of Annexin A1 randomises mitotic spindle orientation, which in turn disrupts epithelial architecture and luminogenesis in three-dimensional cultures of primary mammary epithelial cells. Our findings establish Annexin A1 as an upstream cortical cue that regulates LGN to direct planar cell divisions during mammalian epithelial morphogenesis.

Pan-carcinogenic analysis of Annexin A1 gene in human tumors: A bioinformatics study

Background: Annexin A1 (ANXA1) and cancer appear to be related, based on emerging cell-based or animal research, but pan-cancer analysis is lacking. Objective: By using bioinformatics, we will examine the expression characteristics of the ANXA1 gene in pan-cancers. Methods: In collaboration with TCGA and GEO database, ANXA1 gene was analyzed pan-cancer, and through gene expression analysis, survival analysis, gene variation, immune infiltration, and enrichment analysis, ANXA1 played a role in the pathogenesis of different tumors. Results: A significant correlation has been found between ANXA1 expression and prognosis in some patients with tumors. The expression level of ANXA1 was correlated with the pathological stage of head and neck squamous cell carcinoma (HNSC) and thyroid carcinoma (THCA). The survival rates are related to the expression level of ANXA1 in different tumors. There is a strong correlation between the expression of ANXA1 and immune cell infiltration in some tumors and patients with sarcoma (SARC) and uterine corpus endometrial carcinoma (UCEC) have a higher mutation and amplification rate for the ANXA1 gene. ANXA1 may participate in the occurrence and development of tumor through "proteoglycans in cancer" signal pathways. Conclusion: The ANXA1 gene is involved in the pathogenesis of multiple kinds of tumors, and the study of its pathogenic mechanism may be an effective approach to treating tumors.

Prognostic role of annexin A2 and cancer-associated fibroblasts in advanced non-small cell lung cancer: Implication in epithelial-mesenchymal transition and gefitinib resistance.

Despite advances in treatment of non-small cell lung cancer (NSCLC), its prognosis remains dismal. Development of drug resistance is a major obstacle against success of targeted epidermal growth factor receptor (EGFR) -tyrosine kinase inhibitors (TKI) therapy. This study aimed to assess the prognostic role of annexin A2 (ANXA2) expression, within both tumor cells and stroma, as well as cancer associated fibroblasts (CAFs) in NSCLC and to investigate their potential role in induction of epithelial mesenchymal transition (EMT) and resistance to gefitinib. Immunohistochemistry was performed to evaluate tumoral and stromal ANXA2 expression and α-SMA-stained CAFs in 110 advanced NSCLC patients. Furthermore, STAT3 and E-cadherin mRNA expression was studied by quantitative reverse transcription PCR (qRT-PCR). Both tumoral and stromal ANXA2 as well as CAFs were significantly related to clinical stage IV and malignant pleural effusion, while tumoral ANXA2 was significantly related to poor tumor differentiation. EGFR mutation and high tumoral ANXA2 were independent factors for poor overall survival, whereas high stromal and tumoral ANXA2 and high CAFs were independent predictors for poor progression-free survival. Moreover, high ANXA2 and CAFs were significantly associated with high STAT3 and low E-cadherin mRNA expression. Focusing on EGFR mutated cases, gefitinib resistance was significantly associated with high tumoral and stromal ANXA2, high CAFs, high STAT3 and low E-cadherin. CAFs and ANXA2 could be considered as poor prognostic parameters in advanced NSCLC and are potential factors for gefitinib therapy resistance through EMT induction.

Targeting Annexin A1 as a Druggable Player to Enhance the Anti-Tumor Role of Honokiol in Colon Cancer through Autophagic Pathway

Colon cancer is one of the most common digestive tract malignancies, having the second highest mortality rate among all tumors, with a five-year survival of advanced patients of only 10%. Efficient, targeted drugs are still lacking in treating colon cancer, so it is urgent to explore novel druggable targets. Here, we demonstrated that annexin A1 (ANXA1) was overexpressed in tumors of 50% of colon cancer patients, and ANXA1 overexpression was significantly negatively correlated with the poor prognosis of colon cancer. ANXA1 promoted the abnormal proliferation of colon cancer cells in vitro and in vivo by regulating the cell cycle, while the knockdown of ANXA1 almost totally inhibited the growth of colon cancer cells in vivo. Furthermore, ANXA1 antagonized the autophagic death of honokiol in colon cancer cells via stabilizing mitochondrial reactive oxygen species. Based on these results, we speculated that ANXA1 might be a druggable target to control colon cancer and overcome drug resistance.

Annexin A3 levels in patients with schizophrenia and bipolar disorder

Schizophrenia and bipolar disorder are disorders characterized by alterations in cellular and molecular mechanisms. Annexin A3 (ANXA3) has various effects on neural mechanisms and membrane phospholipid function and both mechanisms are thought to be associated with psychotic disorders. Our study consisted of 93 schizophrenia and bipolar disorder and 52 healthy controls. ANXA3 was analyzed by enzyme-linked immunosorbent assay (ELISA). ANXA3 levels were significantly different between the groups (p<0.001). ANXA3 levels of the control group were higher than ANXA3 levels of schizophrenia and bipolar disorder groups (p<0.001, p<0.001). The ANXA3 levels of the bipolar group were higher than the ANXA3 levels of the schizophrenia group (p<0.001). Laboratory levels of B12, folate, vitamin D, glucose, urea, creatinine, prothrombin time (PT), gamma-glutamyl transferase and lactate dehydrogenase were compared between the groups. B12 levels of the schizophrenia group were lower than B12 levels of bipolar and control groups (p=0.05, p<0.001). Creatinine levels of the schizophrenia group were higher than the creatinine levels of the healthy group (p<0.05). According to posthoc test results, PT levels of the schizophrenia group were higher than PT levels of the healthy group (p<0.05). In line with these findings, we suggest that ANXA3 protein deficiency may have an important role in the physiopathology of schizophrenia and bipolar disorder and may be used as a biomarker in the diagnosis of some psychotic disorders.

The effect of Annexin A5 overexpression on invasiveness and expression of the genes involved in epithelial-mesenchymal transition of HCT 116 cell line.

Epithelial-to-mesenchymal transition (EMT) plays a critical role in colorectal cancer (CRC) metastasis. In the present study, we evaluated the effects of annexin A5 (ANXA5) overexpression on invasiveness as well as the expression of genes involved in EMT of HCT 116 cell line. PCMV6-AC-IRES-GFP plasmid harboring ANXA5 cDNA was constructed. HCT 116 cell line was transfected with recombinant plasmids using Lipofectamine 3000. Fluorescent microscopy was used to determine the efficiency of plasmid transfection. Cell viability was determined using the MTT assay. HCT 116 cell migration was evaluated using wound healing assay and transwell migration assay. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to measure the expression of genes involved in EMT. The results of RT-qPCR showed overexpression of ANXA5 compared to the control group. ANXA5 overexpression had no significant effects on cell viability but significantly decreased the rate of wound closure in the wound healing assay as well as the number of migrated cells in transwell assay. Furthermore, ANXA5 overexpression decreased the expression of N-cadherin, Snail, Slug, MMP-2, and MMP-9 while the expression of E-cadherin increased following ANXA5 overexpression. However, VEGF expression did not significantly change after ANXA5 overexpression. Results of the present study suggest that ANXA5 overexpression might have inhibitory effects on the metastasis of CRC through modulating the expression of EMT- related genes.

Characterizations of annexin A1-interacting proteins in apical membrane and cytosolic compartments of renal tubular epithelial cells

Annexin A1 (ANXA1) is a multifunctional calcium-binding protein that can bind to membrane phospholipids. Under high-calcium condition, ANXA1 expression increases on renal epithelial cell surface, leading to enhanced adhesion of calcium oxalate (CaOx) crystal (stone material) onto the cells. To regulate various cellular processes, ANXA1 interacts with many other intracellular protein partners. However, components of the ANXA1-interacting protein complex remain unclear. Herein, we characterized the interacting complexes of apical membrane (ApANXA1) and cytosolic (cyANXA1) forms of ANXA1 in apical membrane and cytosolic compartments, respectively, of renal epithelial cells under high-calcium condition using proteomic and bioinformatic approaches. After fractionation, the ApANXA1- and CyANXA1-interacting partners were identified by immunoprecipitation followed by nanoLC‑ESI‑Qq-TOF tandem mass spectrometry (IP-MS/MS). The ANXA1-interacting partners that were common in both apical membrane and cytosolic compartments and those unique in each compartment were then analyzed for their physico-chemical properties (molecular weight, isoelectric point, amino acid contents, instability index, aliphatic index, and grand average of hydropathicity), secondary structure (α-helix, β-turn, random coil, and extended strand), molecular functions, biological processes, reactome pathways and KEGG pathways. The data demonstrated that each set of these interacting proteins exhibited common and unique characteristics and properties. The knowledge from this study may lead to better understanding of the ApANXA1 and CyAXNA1 biochemistry and functions as well as the pathophysiology of CaOx kidney stone formation induced by high-calcium condition.

Formyl Peptide Receptor Type 2 Deficiency in Myeloid Cells Amplifies Sepsis-Induced Cardiac Dysfunction

Using a global formyl peptide receptor (Fpr) 2 knockout mouse colony, we have reported the modulatory properties of this pro-resolving receptor in polymicrobial sepsis. Herein, we have used a humanized FPR2 (hFPR2) mouse colony, bearing an intact or a selective receptor deficiency in myeloid cells to dwell on the cellular mechanisms. hFPR2 mice and myeloid cell-specific hFPR2 KO (KO) mice were subjected to cecal ligation and puncture (CLP)-induced polymicrobial sepsis. Compared with hFPR2 mice, CLP caused exacerbated cardiac dysfunction (assessed by echocardiography), worsened clinical outcome, and impaired bacterial clearance in KO mice. This pathological scenario was paralleled by increased recruitment of pro-inflammatory monocytes and reduced M2-like macrophages within the KO hearts. In peritoneal exudates of KO mice, we quantified increased neutrophil and MHC II+ macrophage numbers but decreased monocyte/macrophage and MHC II- macrophage recruitment. hFPR2 upregulation was absent in myeloid cells, and local production of lipoxin A4 was reduced in septic KO mice. Administration of the FPR2 agonist annexin A1 (AnxA1) improved cardiac function in hFPR2 septic mice but had limited beneficial effects in KO mice, in which the FPR2 ligand failed to polarize macrophages toward an MHC II- phenotype. In conclusion, FPR2 deficiency in myeloid cells exacerbates cardiac dysfunction and worsens clinical outcome in polymicrobial sepsis. The improvement of cardiac function and the host immune response by AnxA1 is more effective in hFPR2-competent septic mice.

Screening of an annexin-A2-targeted heptapeptide for pancreatic adenocarcinoma localization.

Annexin A2 (ANXA2) encodes an oncoprotein whose expression has been found to correlate with poorer overall survival (OS) of pancreatic adenocarcinoma (PAAD) patients. Although peptides are available for targeting ANXA2, none of these were initially selected to target this protein specifically. Here, we took ANXA2 as a molecular target for PAAD and employed the phage display technique to screen for a new ANXA2-targeted peptide. The resultant heptapeptide, YW7, was firstly labeled with fluorescein isothiocyanate (FITC) to evaluate its selectivity in cellular uptake, and further with the near-infrared fluorescent (NIRF) dye Cy7 to assess in vivo distribution in a mouse model bearing PANC-1 human pancreatic cancer xenografic tumors. We found that both FITC-YW7 and Cy7-YW7 probes showed significantly higher uptake in PANC-1 cells compared to the HPDE6-C7 pancreatic epithelium cells. Mice intravenously injected with Cy7-YW7 showed higher tumor-to-background ratios (TBRs) (~ 2.7-fold) in tumor tissues compared to those injected with Cy7 alone. Our study suggested that YW7 is a novel peptide targeting ANXA2 and Cy7-YW7 is an NIRF probe potentially useful for the early detection of PAAD.

Bile proteome analysis by high-precision mass spectrometry to examine novel biomarkers of primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of unknown etiology that affects the intra- and extrahepatic bile ducts. The present study examined the utility of a bile proteome analysis using a high-sensitivity mass spectrometer to comprehensively screen for novel PSC biomarkers. Bile endoscopically collected from patients with PSC, common bile duct stones, and biliary tract cancer were subjected to high-precision liquid chromatography/mass spectrometry. Some of the proteins specifically up-regulated in the bile of the PSC group were re-examined by an enzyme-linked immunosorbent assay. A total of 8094 proteins were successfully identified and 332 were specifically up-regulated in the PSC group. The bioinformatics analysis showed that proteins involved in the proliferation and activation of diverse inflammatory cells were up-regulated in the PSC group. A receiver operating characteristic curve analysis showed good area under the curve values for interleukin-8 and annexin A1 (ANXA1) (0.836 and 0.914, respectively). Immunostaining for ANXA1 revealed its strong expression in inflammatory cells infiltrating the peripheral biliary tract in PSC livers. A bile proteome analysis is a useful tool for elucidating the pathogenesis of PSC and developing new diagnostic approaches. Therefore, ANXA1 has potential as a bile biomarker for PSC.

Combination of Small Extracellular Vesicle-Derived Annexin A2 Protein and mRNA as a Potential Predictive Biomarker for Chemotherapy Responsiveness in Aggressive Triple-Negative Breast Cancer

Small extracellular vesicles (sEVs), mainly exosomes, are nanovesicles that shed from the membrane as intraluminal vesicles of the multivesicular bodies, serve as vehicles that carry cargo influential in modulating the tumor microenvironment for the multi-step process of cancer metastasis. Annexin A2 (AnxA2), a calcium(Ca2+)-dependent phospholipid-binding protein, is among sEV cargoes. sEV-derived AnxA2 (sEV-AnxA2) protein is involved in the process of metastasis in triple-negative breast cancer (TNBC). The objective of the current study is to determine whether sEV-AnxA2 protein and/or mRNA could be a useful biomarkers to predict the responsiveness of chemotherapy in TNBC. Removal of Immunoglobulin G (IgG) from the serum as well as using the System Bioscience's ExoQuick Ultra kit resulted in efficient sEV isolation and detection of sEV-AnxA2 protein and mRNA compared to the ultracentrifugation method. The standardized method was applied to the twenty TNBC patient sera for sEV isolation. High levels of sEV-AnxA2 protein and/or mRNA were associated with stage 3 and above in TNBC. Four patients who responded to neoadjuvant chemotherapy had high expression of AnxA2 protein and/or mRNA in sEVs, while other four who did not respond to chemotherapy had low levels of AnxA2 protein and mRNA in sEVs. Our data suggest that the sEV-AnxA2 protein and mRNA could be a combined predictive biomarker for responsiveness to chemotherapy in aggressive TNBC.

SUPPLEMENTARY TABLES AND FIGURES: Bioinformatic analysis of Annexin A1 (ANXA1) protein expression in different types of cancer.

SUPPLEMENTARY TABLES AND FIGURES: Bioinformatic analysis of Annexin A1 (ANXA1) protein expression in different types of cancer.

Interplay of membrane crosslinking and curvature induction by annexins

Efficient plasma membrane repair (PMR) is required to repair damage sustained in the cellular life cycle. The annexin family of proteins, involved in PMR, are activated by Ca2+ influx from extracellular media at the site of injury. Mechanistic studies of the annexins have been overwhelmingly performed using a single annexin, despite the recruitment of multiple annexins to membrane damage sites in living cells. Hence, we investigate the effect of the presence of the crosslinking annexins, annexin A1, A2 and A6 (ANXA1, ANXA2 and ANXA6) on the membrane curvature induction of annexin A4 (ANXA4) in model membrane systems. Our data support a mechanistic model of PMR where ANXA4 induced membrane curvature and ANXA6 crosslinking promotes wound closure. The model now can be expanded to include ANXA1 and ANXA2 as specialist free edge membrane crosslinkers that act in concert with ANXA4 induced curvature and ANXA6 crosslinking.

Annexin A1 (Ac2-26)-dependent Fpr2 receptor alleviates sepsis-induced acute kidney injury by inhibiting inflammation and apoptosis in vivo and in vitro

ObjectivesExcessive inflammatory responses and apoptosis are critical pathologies that contribute to sepsis-induced acute kidney injury (SI-AKI). Annexin A1 (ANXA1), a member of the calcium-dependent phospholipid-binding protein family, protects against SI-AKI through its anti-inflammatory and antiapoptotic effects, but the underlying mechanisms are still largely unknown.MethodsIn vivo, SI-AKI mouse models were established via caecal ligation and puncture (CLP) and were then treated with the Ac2-26 peptide of ANXA1 (ANXA1 (Ac2-26)), WRW4 (Fpr2 antagonist) or both. In vitro, HK-2 cells were induced by lipopolysaccharide (LPS) and then treated with ANXA1 (Ac2-26), Fpr2–siRNA or both.ResultsIn the present study, we found that the expression levels of ANXA1 were decreased, and the expression levels of TNF-α, IL-1β, IL-6, cleaved caspase-3, cleaved caspase-8 and Bax were significantly increased, accompanied by marked kidney tissue apoptosis in vivo. Moreover, we observed that ANXA1 (Ac2-26) significantly reduced the levels of TNF-α, IL-1β and IL-6 and cleaved caspase-3, cleaved caspase-8, FADD and Bax and inhibited apoptosis in kidney tissue and HK-2 cells, accompanied by pathological damage to kidney tissue. Seven-day survival, kidney function and cell viability were significantly improved in vivo and in vitro, respectively. Furthermore, the administration of ANXA1 (Ac2-26) inhibited the CLP- or LPS-induced phosphorylation of PI3K and AKT and downregulated the level of NF-κB in vivo and in vitro. Moreover, our data demonstrate that blocking the Fpr2 receptor by the administration of WRW4 or Fpr2–siRNA reversed the abovementioned regulatory role of ANXA1, accompanied by enhanced phosphorylation of PI3K and AKT and upregulation of the level of NF-κB in vivo and in vitro.ConclusionsTaken together, this study provides evidence that the protective effect of ANXA1 (Ac2-26) on SI-AKI largely depends on the negative regulation of inflammation and apoptosis via the Fpr2 receptor.

Annexin A2 modulates phospholipid membrane composition upstream of Arp2 to control angiogenic sprout initiation.

The intersection of protein and lipid biology is of growing importance for understanding how cells address structural challenges during adhesion and migration. While protein complexes engaged with the cytoskeleton play a vital role, support from the phospholipid membrane is crucial for directing localization and assembly of key protein complexes. During angiogenesis, dramatic cellular remodeling is necessary for endothelial cells to shift from a stable monolayer to invasive structures. However, the molecular dynamics between lipids and proteins during endothelial invasion are not defined. Here, we utilized cell culture, immunofluorescence, and lipidomic analyses to identify a novel role for the membrane binding protein Annexin A2 (ANXA2) in modulating the composition of specific membrane lipids necessary for cortical F-actin organization and adherens junction stabilization. In the absence of ANXA2, there is disorganized cortical F-actin, reduced junctional Arp2, excess sprout initiation, and ultimately failed sprout maturation. Furthermore, we observed reduced filipin III labeling of membrane cholesterol in cells with reduced ANXA2, suggesting there is an alteration in phospholipid membrane dynamics. Lipidomic analyses revealed that 42 lipid species were altered with loss of ANXA2, including an accumulation of phosphatidylcholine (16:0_16:0). We found that supplementation of phosphatidylcholine (16:0_16:0) in wild-type endothelial cells mimicked the ANXA2 knock-down phenotype, indicating that ANXA2 regulated the phospholipid membrane upstream of Arp2 recruitment and organization of cortical F-actin. Altogether, these data indicate a novel role for ANXA2 in coordinating events at endothelial junctions needed to initiate sprouting and show that proper lipid modulation is a critical component of these events.

Annexin A1 Is Associated with Adverse Clinical Outcomes in Patients with COVID-19.

Severe coronavirus disease 2019 (COVID-19) is characterized by hyperinflammation, vascular damage, and hypercoagulability. Insufficient responses of Annexin A1 (AnxA1), a pro-resolving inhibitor of neutrophil infiltration and activation, might contribute to a severe course of the disease. We longitudinally evaluated AnxA1's role in terms of inflammation, vascular damage, and clinical outcomes in a large prospective cohort of patients with COVID-19. AnxA1 was measured at presentation and during follow-up in the sera of 220 consecutive patients who presented at our hospital during the first wave. AnxA1 was significantly higher in the moderate and severe cases of COVID-19 compared to the healthy controls. Elevated AnxA1 was associated with markers of inflammation and endothelial damage. AnxA1 was significantly higher in patients with thrombotic events and ICU admission. Multivariable logistic regression indicated baseline AnxA1 (per ten units) as a predictor of thrombotic events. Linear mixed models predicted that AnxA1 tended to increase more steeply over time in patients without adverse events, with a statistically significant rise in patients without thrombotic events. These findings might reflect an insufficient increase in AnxA1 as a response to the excessive hyperinflammation in COVID-19. Future studies should evaluate whether hyperinflammation could be reduced through the administration of human recombinant AnxA1 or Ac2-26 peptide.

Sirtuin 5 aggravates microglia-induced neuroinflammation following ischaemic stroke by modulating the desuccinylation of Annexin-A1

BackgroundMicroglia-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.MethodsMice 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.ResultsIn 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.ConclusionsCollectively, 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.

Proteomic Portrait of Human Lymphoma Reveals Protein Molecular Fingerprint of Disease Specific Subtypes and Progression.

The online version contains supplementary material available at 10.1007/s43657-022-00075-w.

Multi-omics analyses identify molecular signatures with prognostic values in different heart failure aetiologies

BackgroundHeart failure (HF) is the leading cause of morbidity and mortality worldwide, and there is an urgent need for more global studies and data mining approaches to uncover its underlying mechanisms. Multiple omics techniques provide a more holistic molecular perspective to study pathophysiological events involved in the development of HF. MethodsIn this study, we used a label-free whole myocardium multi-omics characterization from three commonly used mouse HF models: transverse aortic constriction (TAC), myocardial infarction (MI), and homozygous Phospholamban-R14del (PLN-R14Δ/Δ). Genes, proteins, and metabolites were analysed for differential expression between each group and a corresponding control group. The core transcriptome and proteome datasets were used for enrichment analysis. For genes that were upregulated at both the RNA and protein levels in all models, clinical validation was performed by means of plasma level determination in patients with HF from the BIOSTAT-CHF cohort. ResultsCell death and tissue repair-related pathways were upregulated in all preclinical models. Fatty acid oxidation, ATP metabolism, and Energy derivation processes were downregulated in all investigated HF aetiologies. Putrescine, a metabolite known for its role in cell survival and apoptosis, demonstrated a 4.9-fold (p < 0.02) increase in PLN-R14Δ/Δ, 2.7-fold (p < 0.005) increase in TAC mice, and 2.2-fold (p < 0.02) increase in MI mice. Four Biomarkers were associated with all-cause mortality (PRELP: Hazard ratio (95% confidence interval) 1.79(1.35, 2.39), p < 0.001; CKAP4: 1.38(1.21, 1.57), p < 0.001; S100A11: 1.37(1.13, 1.65), p = 0.001; Annexin A1 (ANXA1): 1.16(1.04, 1.29) p = 0.01), and three biomarkers were associated with HF-Related Rehospitalization, (PRELP: 1.88(1.4, 2.53), p < 0.001; CSTB: 1.15(1.05, 1.27), p = 0.003; CKAP4: 1.18(1.02, 1.35), P = 0.023). ConclusionsCell death and tissue repair pathways were significantly upregulated, and ATP and energy derivation processes were significantly downregulated in all models. Common pathways and biomarkers with potential clinical and prognostic associations merit further investigation to develop optimal management and therapeutic strategies for all HF aetiologies.