To evaluate the predictive role of serum amyloid A (SAA) levels and their association with antiphospholipid antibodies (APA) and coagulation markers such as lupus anticoagulants (LA), anti-cardiolipin (ACA), protein C (PC) deficiency, protein S (PS) deficiency, and antithrombin III (ATIII) deficiency in recurrent pregnancy loss (RPL). This prospective case-control study comprised two groups: the study group (n = 88) included women with recurrent pregnancy loss at Mansoura University Hospital between January 2019 and December 2020, and the control group (n = 52) included women without obstetric or medical complications. Demographic, clinical, and laboratory data, including serum samples collected at 10 weeks of gestation, were collected from all participants. The study measured SAA levels, lupus anticoagulants, anti-cardiolipin, protein C, protein S, and antithrombin III levels. The SAA level was significantly elevated in the recurrent pregnancy loss group compared to that in the control group. Lupus anticoagulant positive, anti-cardiolipin positive Immunoglobulin M (IgM), and deficiencies in protein C, protein S, and antithrombin III were significantly observed in patients with RPL (p < 0.05). The SAA levels were significantly elevated in both LA-positive and ACA-positive IgM patients. The receiver operating characteristic (ROC) curve analysis demonstrated that at SAA > 24.8 for the prediction of recurrent pregnancy loss, sensitivity was 98.86%, and specificity was 92.31%. Positive and negative predictive values were 95.6% and 98.0%, respectively. The area under the curve = 0.971 (0.927-0.992). SAA is associated with recurrent pregnancy loss and may therefore serve as a potential predictor of this condition. The observed elevation in SAA levels could be primary or secondary to the inflammatory response that promotes thrombotic activity in RPL patients at risk of APA, Protein S, Protein C, and ATIII deficiencies. Implementing SAA screening during pregnancy may facilitate the identification of individuals who could potentially benefit from novel treatment strategies.

Endometriosis is a common condition among women, characterized by chronic pain and infertility, presenting significant challenges for clinicians. This study aims to identify potential druggable targets to offer new therapeutic approaches.

We utilized the summary-data-based Mendelian randomization (SMR) method to investigate the causal relationships between druggable genes that encode plasma proteins and endometriosis. The data sources included the deCODE database, the UKB-PPP, and the FinnGen database. Colocalization analysis was used to identify whether candidate genes and the disease share a common causal genetic variant. Finally, we measured the protein abundance and relative mRNA expression levels of targeted druggable genes in the plasma and peripheral blood mononuclear cells (PBMCs) of endometriosis patients using ELISA and RT-qPCR.

By integrating the results of SMR and colocalization analyses, we found that EPHB4 is strongly associated with the risk of endometriosis, with higher levels of EPHB4 correlating with an increased risk of the condition (PFDR < 0.05, PPH4 = 0.99). RSPO3 is moderately associated, with higher levels of RSPO3 correlating with an increased risk of endometriosis (PFDR < 0.001, PPH4 = 0.78). CD109, SAA1, SAA2, FSHB, and SEZ6L2 are weakly associated with endometriosis, with higher levels of FSHB and SEZ6L2 correlating with an increased risk of endometriosis, and higher levels of CD109, SAA1, and SAA2 correlating with a decreased risk of endometriosis (PFDR < 0.05, PPH4 < 0.6). ELISA and RT-qPCR analyses showed that the EPHB4 protein abundance in plasma and mRNA expression levels in PBMCs were significantly higher in the endometriosis group compared to the control group (P-value < 0.05).

We found that the druggable genes EPHB4, CD109, SAA1, SAA2, FSHB, and SEZ6L2 may be associated with the pathogenesis of endometriosis and are potential therapeutic targets for drug treatment. However, this preliminary study is limited by sample size and population diversity, requiring further validation to confirm the reliability of these findings.

Ischemia-reperfusion injury (IRI) during kidney transplantation is linked to oxidative stress induced by excessive reactive oxygen species (ROS), which causes the injury of transplanted kidney, leading to further intensified organ shortages. Protein-based antioxidants have been developed for ROS scavenging via cascade biocatalyst. The in situ growth of metal nanozymes on proteins effectively decreases the steric hindrance between active sites, improving the efficiency of cascade biocatalysts. However, the poor stability of protein during the process of preparation and intracellular delivery leads to low therapeutic effects. In this study, three different functional polymers are conjugated to SOD for the formation of micelles. Surprisingly, it is found that the conjugated ultra-acid sensitive polymer efficiently preserves the enzymatic activity of SOD, due to great endo/lysosomal escape capacity. Subsequently, SOD micelles (SOE) are used as a template to prepare SOE-Pt0 (SOEP) through in situ growth of Pt0 with vicinal enzymatic active sites. The preparation process minimally impacts on the activity of SOD, owing to improved stability. The system exhibits effective cascade ROS scavenging, significantly reducing kidney damage and inflammation caused by IRI. The research offers a novel approach for addressing IRI challenges in organ transplantation and provides a promising strategy to mitigate organ shortages.

Kawasaki disease (KD) is an acute systemic vasculitis that primarily affects coronary arteries, and delayed diagnosis increases the risk of cardiovascular complications. Biomarkers are essential for improving diagnostic accuracy, especially in atypical cases. Gingival crevicular fluid (GCF), derived from periodontal tissues, contains serum components and inflammatory mediators, and has emerged as a valuable biofluid for systemic disease diagnosis. Previous studies suggest GCF protein profiles reflect immune status and metabolic disorders, such as type 2 diabetes. Given the immune-related nature of KD, GCF protein composition may also be altered, yet no studies have systematically explored GCF biomarkers in KD. This study uses DIA and MRM-MS proteomics to identify potential GCF biomarkers for KD diagnosis.

Twenty-seven patients with KD were enrolled in this study, and 18 healthy volunteers were recruited as the control group. GCF samples were collected from the KD patients, who formed the experimental group, before they received intravenous immunoglobulin treatment. Data-independent acquisition (DIA) quantitative proteomics mass spectrometry was performed on the GCF samples to analyze the protein expression profiles in both groups. DEPs were identified and subjected to functional enrichment analysis using KEGG and GO. Protein-protein interaction (PPI) analysis was conducted for all detected DEPs. Finally, multiple reaction monitoring mass spectrometry (MRM-MS) was used to validate the selected DEPs.

A total of 197 DEPs were identified in GCF between the KD group and the normal control group, with 174 upregulated and 23 downregulated proteins. Functional enrichment analysis revealed that cellular and metabolic processes were the most significantly altered biological processes, while binding and catalytic activity were the most affected molecular functions. Pathway analysis further highlighted the NOD-like receptor signaling pathway, protein processing in the endoplasmic reticulum, and the influenza pathway as the most significantly enriched pathways. In the PPI network, EIF2AK2, B2M, and GBP1 were identified as key hub proteins, suggesting their potential regulatory roles in KD pathophysiology. Finally, MRM-MS confirmed the expression patterns of 12 DEPs (IFIT3, UB2L6, HP, A1AT, HSP90AA1, HNRPC, HSP90AB1, SAA1, MX1, B2M, FKBP4, and TRAP1), thereby demonstrating high consistency with the DIA results and further validating the DEPs' potential as biomarkers for KD.

Our findings suggest that 12 proteins in GCF could serve as potential biomarkers for the early diagnosis of KD. Additionally, the molecular analysis revealed a close association between KD and gingival inflammation, offering new insights into KD's pathophysiology and potential directions for improved diagnosis and treatment.

Fungal keratitis (FK) is a severe ocular infection, with its underlying molecular mechanisms remaining incompletely understood. This study aimed to identify and investigate key genes involved in immune-inflammatory responses associated with FK pathogenesis using bioinformatics and in vitro assays.

Transcriptomic data from the Gene Expression Omnibus (GEO) database (GSE58291) were analyzed using the limma package to identify differentially expressed genes (DEGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to evaluate significant biological processes and pathways related to DEGs. Weighted gene co-expression network analysis (WGCNA) identified gene modules linked with FK-associated DEGs, and Venn diagram analysis highlighted core genes. Receiver operating characteristic (ROC) analysis assessed diagnostic potential. Immune cell composition was analyzed using CIBERSORT, and correlations between key genes and immune cells were evaluated. In vitro, human corneal epithelial cells (HCEC) were stimulated with Aspergillus fumigatus (A.F.), and pro-inflammatory cytokine expression (IL-1β, TNF-α, IL-6) was assessed using enzyme-linked immunosorbent assay (ELISA). Western blot and quantitative real-time polymerase chain reaction (RT-qPCR) analyzed FOXO3a phosphorylation and gene expression changes post-SAA1 siRNA transfection.

A total of 101 DEGs were identified, with WGCNA revealing 6 co-expression network modules, with significant associations noted in yellow and black modules. Nine shared genes were identified in DEGs and modules, with SAA1 strongly linked to FK pathogenesis. SAA1 expression was positively correlated with neutrophils, T cells CD4 memory activated, T cells gamma delta, and activated mast cells. Upon stimulation with A.F., cytokine expression increased, peaking at 24 h. Inhibition of SAA1 reduced FOXO3a phosphorylation and pro-inflammatory cytokine levels, underscoring SAA1's role in FK inflammation via FOXO3a regulation.

SAA1 is a key gene in FK, promoting inflammation by modulating FOXO3a phosphorylation. This highlights its potential as a therapeutic target in managing FK-related inflammation.

Serum amyloid A (SAA), a small lipophilic plasma protein elevated in inflammation, is a precursor of amyloid A (AA) amyloidosis, the major life-threatening complication of chronic inflammation in animals and humans. Although heparan sulfate (HS) is a potent amyloid agonist, particularly in AA amyloidosis, therapeutic targeting of SAA-HS interactions using a small-molecule HS/heparin decoy was unsuccessful. To understand molecular underpinnings, we used recombinant lipid-free human and murine SAA1 and human SAA2 to explore their interactions with various glycosaminoglycans at pH 5.5-7.4 during amyloid formation, from native protein to amyloid oligomers and fibrils. Effects of pH and glycosaminoglycan sulfation/charge supported by prior computational studies indicate electrostatic origin of SAA-glycosaminoglycan interactions. HS/heparin can promote amyloidogenesis by inducing non-native β-sheet and apparently causing liquid droplet formation in SAA in solution. Structural and binding studies by spectroscopy and ELISA reveal previously unknown synergy between amyloid formation and heparin/HS binding by SAA. We propose that this synergy potentially extends to other protein amyloids and stems from longitudinal binding of HS polyanions to basic residue arrays on amyloid oligomers or fibrils. This binding mode explains our finding that a minimal heparin chain length exceeding 20 monosaccharides is necessary to compete with HS for binding to amyloid oligomers. The results help explain prior failure of a small-molecule drug in targeting of SAA-HS interactions and consider alternative HS-targeting approaches for AA and, potentially, other amyloid diseases.

Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection, has an approximately 25% in-hospital mortality rate. Identifying early biomarkers of pediatric sepsis is crucial for improving outcomes. This study explored the differential expression of peptides in patients with sepsis compared to healthy controls and those with common infections using plasma peptidomic analysis. Blood samples were collected from 10 pediatric patients with sepsis admitted to Hunan Children's Hospital in 2021, along with 20 age- and sex-matched healthy controls and five children with common infections. Differential peptide precursor proteins underwent gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses and protein-protein interaction analysis using the STRING database. Intotal, 3149 endogenous peptides corresponding to 480 precursor proteins were identified. Compared to the healthy group, the sepsis group exhibited 1113 differentially expressed peptides, with 880 upregulated and 233 downregulated. Compared with the common infection group, the sepsis group showed 181 upregulated and 86 downregulated peptides. These differences were primarily in the humoral immune response and complement and coagulation cascades. This study identified specific alterations in peptide expression in the plasma of patients with sepsis, most notably in peptides related to SAA1, complement C3, hemoglobin, and haptoglobin. These peptides are involved in the acute inflammatory response, complement system, and free hemoglobin pathways, indicating their crucial roles in sepsis pathology. These findings provide new insights into the mechanisms of sepsis and suggest potential applications for these peptides in sepsis diagnosis and treatment, to enhance early diagnosis and therapeutic outcomes.

AA amyloidosis is a prototypic example of systemic amyloidosis: it results from the prolonged overproduction of SAA protein produced in response to chronic inflammation. AA amyloidosis primarily affects the kidneys, liver, spleen, gastrointestinal tract, leading to a variety of symptoms. First, this review examines AA amyloidosis in humans, focusing on pathogenesis, clinical presentation, and diagnosis and then in animals. In fact AA amyloidosis is the only systemic amyloidosis that has been largely documented in a remarkable number of vertebrate species: mammals, birds, and fishes, especially in individuals with comorbidities, chronic stress, or held in captivity. Secondly, here, we summarise independent sets of evidence obtained on different animal species, exploring the possible transmissibility of AA amyloidosis especially in crowded or confined populations. Finally, biochemical and structural data on native SAA and on AA amyloid fibrils from human, murine, and cat ex vivo samples are discussed. The available structural data depict a complex scenario, where SAA can misfold forming highly different amyloid assemblies. This review highlights the complexity of AA amyloidosis, emphasising the need for further research into its spread in the animal kingdom, its structural aspects, and pathogenetic mechanisms to evaluate its impact on human and animal health.

Serum amyloid A1 (SAA1) is an apolipoprotein which is involved in amyloid A amyloidosis (AA) by forming fibrils. The process of fibrillation is still being explored and holds challenges in recombinant expression and purification of SAA1. This study deals with the preferable approach for the expression and purification of SAA1 which is normally toxic and unstable to express without using any fusion-tag. Complete soluble expression of SAA1 was obtained without the use of additional tag, in terrific broth, supplemented with 3 % ethanol at 30 °C. Soluble fraction of SAA1 was initially treated with salting-out using ammonium sulphate giving 1.5 M salt concentration to avoid SAA1 protein precipitation along with unwanted proteins. The soluble fraction of SAA1 after salting-out was purified by two individual chromatographic approaches: One anion exchange and second reverse phase chromatography. The yield of purified SAA1 was 3 times greater by anion exchange than reverse phase chromatography. MALDI-TOF analysis of purified SAA1 showed 11813 Da for intact protein and proteome analysis revealed greater than 90 % sequence coverage by MASCOT. The subunit interaction showed hexamer form at basic pH which was analyzed by size exclusion chromatography. The fibrillation activity of SAA1 was found to be 10-15 times higher in basic media at 43 °C than 37 °C. Our research demonstrates successful expression and purification of wild-type human recombinant SAA1. The cost-effective radical approach employed for purification of SAA1 is crucial for thorough protein characterization particularly, mechanisms of protein aggregation involved in amyloidosis.

The spread of Porcine contagious pleuropneumonia (PCP), a severe disease that occurs in pigs caused by Actinobacillus pleuropneumoniae (APP), remains a threat to the porcine farms and has been known to cause severe economic losses. Serum amyloid A (SAA) is an acute-phase protein rapidly expressed in response to infection and inflammation in vertebrates. This study aimed to investigate the function of SAA3 in bacterial infections. Here, APP was used to infect porcine alveolar macrophages (3D4/21), pigs, and mice. The results showed that the expression level of SAA3 was significantly up-regulated in APP-infected 3D4/21 cells, as well as pigs and mice infected with APP. In SAA3-overexpressing (SAA3-OE) cells, the expression of IL-1β, IL-6, and TNF-α were also up-regulated, while silencing of SAA3 reversed these effects. Furthermore, the levels of APP were substantially up-regulated in the culture supernatant of SAA3-OE cells, with significant down-regulation in siRNA-SAA3 cells culture supernatants. Also, SAA3-OE enhanced the adhesion and invasion of APP-infected target cells. These findings suggest that porcine SAA3 up-regulated cytokine expression, with increased SAA3 expression exacerbating inflammation. Notably, SAA3 promoted the growth of APP during the logarithmic growth phase. This created favorable conditions for APP growth and promoted its proliferation, adhesion, and invasion. These findings provide insights into the role of porcine SAA3 in the course of bacterial infection.

Abnormal endometrial extracellular matrix (ECM) remodeling compromises endometrial receptivity and diminishes the probability of a successful live birth. Serum amyloid A1 (SAA1), a modulator of inflammation, is elevated in the circulation of polycystic ovary syndrome (PCOS) patients and involved in ECM remodeling during tissue repair. However, the specific role of SAA1 in endometrial ECM remodeling and subsequent risk of pregnancy loss in PCOS patients remains unclear.

To examine the role and underlying mechanism of SAA1 in ECM remodeling in the endometrium of PCOS patients.

Serum samples from PCOS and control patients were utilized to investigate the relationship between the abundance of SAA1 and pregnancy loss. Human endometrial tissues and primary human endometrial stromal cells were used to examine the role and underlying mechanism of SAA1 in ECM remodeling.

Serum SAA1 concentration was elevated and could serve as an independent risk of pregnancy loss in PCOS patients. Increased SAA1 abundance was also observed in endometrium obtained from these patients. Further mechanistic studies showed that SAA1 stimulated collagen I chains synthesis (COL1A1 and COL1A2) in endometrial stromal cells, suggesting excessive SAA1 may contribute to endometrial ECM remodeling, resulting in a nonsupportive environment for ongoing pregnancy. This effect was abolished by either a toll-like receptor 2/4 antagonist or a nuclear factor κB inhibitor.

The locally elevated levels of SAA1 in endometrium contribute to ECM overdeposition by inducing collagen I synthesis in PCOS patients, which may hamper embryo implantation and increase the risk of pregnancy loss. These observations highlight the crucial role of heightened SAA1 in orchestrating endometrial dysfunction and shed light on potential therapeutic avenues for improving reproductive outcomes in PCOS patients.

Alkaptonuria (AKU) is a rare metabolic disorder characterized by the accumulation of homogentisic acid (HGA), leading to progressive ochronosis and joint degeneration. While much is known about HGA's role in tissue damage, the molecular mechanisms underlying acute inflammation in AKU remain poorly understood. Serum amyloid A (SAA) proteins are key mediators of the inflammatory response, yet their potential as biomarkers for inflammation in AKU has not been explored. This study investigated the role of the SAA1.1 allele as a biomarker for the severity of acute inflammation in AKU. Data from the ApreciseKUre Precision Medicine Ecosystem were analyzed to assess the relationship between SAA1 allelic variants and inflammatory markers. Molecular dynamics simulations compared the structural dynamics of SAA1.1 and SAA1.2 isoforms, with standard modeling and analysis pipelines employed. Using a clinomics approach, we showed that AKU patients expressing the SAA1.1 allele have significantly higher acute inflammation-related markers. Extensive molecular dynamics simulations revealed that the SAA1.1 isoform lent high structural instability of the C-terminal domain, accelerating the formation of amyloid fibrils and exacerbating the inflammatory condition. These findings would identify the SAA1.1 allele as a novel genetic biomarker for the progression of secondary amyloidosis in AKU and its severity. Furthermore, new molecular insights into the inflammatory mechanisms of AKU were provided, suggesting potential therapeutic approaches aimed at stabilizing SAA1.1 protein and preventing amyloid fibril formation, with significant implications in AKU and precision medicine strategies for SAA-related diseases.

Research on serum amyloid A (SAA) has seen major advancement in recent years with combined approaches of structural analysis and genetically altered mice. Initially identified as an acute-phase reactant, SAA is now recognized as a major player in host defense, inflammation, lipid metabolism and tumor metastasis. SAA binding and the neutralization of LPS attenuate sepsis in mouse models. SAA also displays immunomodulatory functions in Th17 differentiation and macrophage polarization, contributing to a pro-metastatic tumor microenvironment. In spite of the progress, the regulatory mechanisms for these diverse functions of SAA remain unclear. This review provides a brief summary of recent advances in SAA research on immunity, inflammation, tumor microenvironment and in vivo models.

Wnt proteins are critical signaling molecules in developmental processes across animals. Despite intense study, their evolutionary roots have remained enigmatic. Using sensitive sequence analysis and structure modeling, we establish that the Wnts are part of a vast assemblage of domains, the Lipocone superfamily, defined here for the first time. It includes previously studied enzymatic domains like the phosphatidylserine synthases (PTDSS1/2) and the TelC toxin domain from Streptococcus intermedius , the enigmatic VanZ proteins, the animal Serum Amyloid A (SAA) and a further host of uncharacterized proteins in a total of 30 families. Though the metazoan Wnts are catalytically inactive, we present evidence for a conserved active site across this superfamily, versions of which are consistently predicted to operate on head groups of either phospholipids or polyisoprenoid lipids, catalyzing transesterification and phosphate-containing head group severance reactions. We argue that this superfamily originated as membrane proteins, with one branch (including Wnt and SAA) evolving into soluble versions. By comprehensively analyzing contextual information networks derived from comparative genomics, we establish that they act in varied functional contexts, including regulation of membrane lipid composition, extracellular polysaccharide biosynthesis, and biogenesis of bacterial outer-membrane components, like lipopolysaccharides. On multiple occasions, members of this superfamily, including the bacterial progenitors of Wnt and SAA, have been recruited as effectors in biological conflicts spanning inter-organismal interactions and anti-viral immunity in both prokaryotes and eukaryotes. These findings establish a unifying theme in lipid biochemistry, explain the origins of Wnt signaling and provide new leads regarding immunity across the tree of life.

Mitochondria dysfunction is implicated in cell death, inflammation, and autoimmunity. During viral infections, some viruses employ different strategies to disrupt mitochondria-dependent apoptosis, while others, including SARS-CoV-2, induce host cell apoptosis to facilitate replication and immune system modulation. Given mitochondrial DNAs (mtDNA) role as a pro-inflammatory damage-associated molecular pattern in inflammatory diseases, we examined its levels in the serum of COVID-19 patients and found it to be high relative to levels in healthy donors. Furthermore, comparison of serum protein profiles between healthy individuals and SARS-CoV-2-infected patients revealed unique bands in the COVID-19 patients. Using mass spectroscopy, we identified over 15 proteins, whose levels in the serum of COVID-19 patients were 4- to 780-fold higher. As mtDNA release from the mitochondria is mediated by the oligomeric form of the mitochondrial-gatekeeper-the voltage-dependent anion-selective channel 1 (VDAC1)-we investigated whether SARS-CoV-2 protein alters VDAC1 expression. Among the three selected SARS-CoV-2 proteins, small envelope (E), nucleocapsid (N), and accessory 3b proteins, the E-protein induced VDAC1 overexpression, VDAC1 oligomerization, cell death, and mtDNA release. Additionally, this protein led to mitochondrial dysfunction, as evidenced by increased mitochondrial ROS production and cytosolic Ca2+ levels. These findings suggest that SARS-CoV-2 E-protein induces mitochondrial dysfunction, apoptosis, and mtDNA release via VDAC1 modulation. mtDNA that accumulates in the blood activates the cGAS-STING pathway, triggering inflammatory cytokine and chemokine expression that contribute to the cytokine storm and tissue damage seen in cases of severe COVID-19.

Non-unions are fractures that do not heal properly, resulting in a false joint formation at the fracture site. This condition leads to major health issues and imposes a burden on national healthcare systems. The etiology of non-unions is still not fully understood; therefore, we aimed to identify potential systemic factors that may contribute to their formation.

We conducted a cross-sectional concomitant proteomic and metabolomic pilot study of blood plasma in patients with non-unions (N = 11) and compared them with patients with bone fracture in the normal active healing phase (N = 12).

We found five significantly upregulated proteins in the non-union group: immunoglobulin heavy variable 3-74, immunoglobulin lambda variable 2-18, low-density lipoprotein receptor-related protein 4, zinc-alpha-2-glycoprotein, and serum amyloid A-1 protein; and we found one downregulated protein: cystatin-C. The metabolomic study found differences in alanine, aspartate and glutamate metabolism pathways between two groups.

The combined results of proteomic and metabolomic analyses suggest that the dysregulation of lipid metabolism may contribute to non-union formation.

Infection is one of the leading causes of death in patients with hematologic cancers. Hematologic cancer patients with compromised immune systems are already susceptible to infections, which come on even more rapidly and are difficult to control after they develop neutrophil deficiencies from high-dose chemotherapy. After patients have developed an infection, the determination of the type of infection becomes a priority for clinicians. In this review, we summarize the biomarkers currently used for the prediction of infections in patients with hematologic cancers; procalcitonin, CD64, cytokines, and CD14 et al. can be used to determine bacterial infections, and (1-3)-β-D-glucan and galactomannan et al. can be used as a determination of fungal infections. We have also focused on the use of metagenomic next-generation sequencing in infections in patients with hematologic cancers, which has excellent clinical value in infection prediction and can detect microorganisms that cannot be detected by conventional testing methods such as blood cultures. Of course, we also focused on infection biomarkers that are not yet used in blood cancer patients but could be used as a future research direction, e.g., human neutrophil lipocalin, serum amyloid A, and heparin-binding protein et al. Finally, clinicians need to combine multiple infection biomarkers, the patient's clinical condition, local susceptibility to the type of infection, and many other factors to make a determination of the type of infection.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly related to nutrition. However, only a few human and animal studies have tested the association between MASLD and dairy consumption and the effect of milk fat on liver damage. Therefore, we aimed at testing the association between consumption of dairy product and the incidence of MASLD and fibrosis markers in humans, and the effect of milk fat vs. other fats on MASLD in animal studies.

A prospective 7-year follow-up cohort study was performed including baseline and follow-up fasting blood tests, liver evaluation and a face-to-face interview on health status and behaviour using structured questionnaires. MASLD was determined by ultrasonography or by controlled attenuation parameter (CAP), and liver fibrosis by FibroTest™ or FibroScan®. An animal study was performed in which 6-week-old C57BL/6j male mice were fed a high-fat diet (HFD) consisting of lard, soybean oil, and milk fat for 12 weeks. Metabolic impairment was assessed during the animal experiment, and serum advanced glycation end-products (AGEs) and liver damage were evaluated.

A total of 316 patients were included in the prospective cohort. In multivariable analysis, high consumption of low-medium fat low-sugar dairy products (g/day above the baseline sex-specific median) was associated with a lower risk for MASLD incidence (OR 0.42, 95% CI 0.18-0.95, p = 0.037) or incidence/persistence at follow-up (OR 0.58, 0.34-0.97, p = 0.039). Constantly high consumption of high-fat low-sugar dairy products was associated with greater odds for new onset/persistence of MASLD. Neither low-medium nor high-fat dairy consumption was related to fibrosis markers. In mice, all HFDs induced similar weight gain and steatosis and did not affect liver enzymes. Milk fat increases serum cholesterol and AGEs levels more than lard or soybean oil.

Low-medium fat low-sugar dairy products may be protective and should be preferred over high-fat dairy to prevent MASLD. HFDs from different fat sources with a wide spectrum of fatty acid saturation content are equally deleterious.

MASLD is related to nutrition, but evidence of an association between high-fat and low-fat dairy products is lacking, therefore, we evaluated this association by performing experimental studies in mice and an observational human study. For MASLD prevention, a differential effect based on the type of dairy products should be considered: low-medium fat low-sugar dairy products were found to be protective, in contrast high-fat dairy and generally high-fat diets may be harmful. It would be advisable to prefer low-fat low-sugar dairy products and minimise intake of high-fat dairy products; however, additional evidence is needed to allow generalisability of our findings.

Serum amyloid A (SAA) is one of the most important precursor amyloid proteins discovered during the study of amyloidosis, but its underlying aggregation mechanism has not yet been well elucidated. Since SAA aggregation is a key step in the pathogenesis of AA amyloidosis, amyloid inhibitors can be used as a tool to study its pathogenesis. Previously, we reported a novel microliter-scale high-throughput screening (MSHTS) system for screening amyloid β (Aβ) aggregation inhibitors based on quantum dot (QD) fluorescence imaging technology. In this study, we report the aggregation of human SAA (hSAA) in phosphate-buffered saline, in which we successfully visualized hSAA aggregation by QD using fluorescence microscopy and confocal microscopy. Two-dimensional and three-dimensional image analyses showed that most aggregations were observed at 40 μM hSAA, which was the optimal aggregation concentration in vitro. The accuracy of this finding was verified by a Thioflavin T assay. The transmission electron microscopy results showed that QD uniformly bound to hSAA aggregation. hSAA aggregation inhibitory activity was also evaluated by rosmarinic acid (RA). The results showed that RA, which is a compound with high inhibitory activity against Aβ aggregation, also exhibited high inhibitory activity against 40 μM hSAA. These results indicate that the MSHTS system is an effective tool for visualizing hSAA aggregation and for screening highly active inhibitors.

Patients who receive thoracic radiotherapy may suffer from radiation-induced lung injury, but the treatment options are limited as the underlying mechanisms are unclear. Using a mouse model of right thorax irradiation with fractionated doses of X-rays for three consecutive days (8 Gy/per day), this study found that the thoracic irradiation (Th-IR) induced tissue injury with aberrant infiltration of macrophages, and it significantly increased the secretion of TNF-α, IL-1β, IL-6, TGF-β1 and serum amyloid A (SAA) in mice. Interestingly, SAA could activate macrophages and then induce epithelial-mesenchymal transition (EMT) of lung epithelial cells and fibrosis progression in lung tissue. Mechanistically, SAA enhanced the transient binding of FPR2 to Rac1 protein and further activated NF-κB signaling pathway in macrophages. Inhibition of FPR2 significantly reduced pulmonary fibrosis induced by SAA administration in mice. In addition, cimetidine could reduce the level of SAA release after irradiation and attenuate the lung injury induced by SAA or Th-IR. In conclusion, our results demonstrated that SAA activated macrophages via FPR2/Rac1/NF-κB pathway and might contribute to the Th-IR induced lung injury, which may provide a new strategy to attenuate radiation-induced adverse effects during radiotherapy.

Alkaptonuria (AKU) is a rare autosomal recessive metabolic disorder caused by mutations in the homogentisate 1,2-dioxygenase (HGD) gene, leading to the accumulation of homogentisic acid (HGA), causing severe inflammatory conditions. Recently, the presence of serum amyloid A (SAA) has been reported in AKU tissues, classifying AKU as novel secondary amyloidosis; AA amyloidosis is characterized by the extracellular tissue deposition of fibrils composed of fragments of SAA. AA amyloidosis may complicate several chronic inflammatory conditions, like rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, chronic infections, neoplasms, etc. Treatments of AA amyloidosis relieve inflammatory disorders by reducing SAA concentrations; however, no definitive therapy is currently available. SAA regulation is a crucial step to improve AA secondary amyloidosis treatments. Here, applying a comprehensive in vitro and in silico approach, we provided evidence that HGA is a disruptor modulator of SAA, able to enhance its polymerization, fibril formation, and aggregation upon SAA/SAP colocalization. In silico studies deeply dissected the SAA misfolding molecular pathway and SAA/HGA binding, suggesting novel molecular insights about it. Our results could represent an important starting point for identifying novel therapeutic strategies in AKU and AA secondary amyloidosis-related diseases.

Lichen sclerosus urethral stricture disease (LS USD) is a refractory and progressive disease primarily affecting the anterior urethra in males. Various potential etiological factors, such as genetics, autoimmunity, infection, and exposure to infectious urine, have been suggested. However, the accurate etiology of LS in the male urethra remains unclear.

In this study, we conducted single-cell RNA sequencing to identify the transcriptional profiles of three patients with LS USD and three patients with non-LS USD. Immunofluorescence was used to confirm the single-cell sequence results.

Our study revealed distinct subsets of vein endothelial cells (ECs), smooth muscle cells (SMCs), and fibroblasts (FBs) with high proportions in LS USD, contributing to the tissue microenvironment primarily involved in proinflammatory and immune responses. In particular, FBs displayed a unique subset, Fib7, which is exclusively present in LS USD, and exhibited high expression levels of SAA1 and SAA2. The accumulation of macrophages, along with the dysregulated ratios of M1/M2-like phenotype macrophages, may be engaged in the pathogenesis of LS USD. Through cell-cell communication analysis, we identified significant interactions involving CXCL8/ACKR1 and CCR7/CCL19 in LS USD. Remarkably, Fib7 exhibited exclusive communication with IL-1B macrophages through the SAA1/FPR2 receptor-ligand pair.

Our study provides a profound understanding of the tissue microenvironment in LS USD, which may be valuable for understanding the pathogenesis of LS USD.

Acquired brain injury is an urgent situation that requires rapid diagnosis and treatment. Magnetic resonance imaging (MRI) and computed tomography (CT) are required for accurate diagnosis. However, these methods are costly and require substantial infrastructure and specialized staff. Circulatory biomarkers of acute brain injury may help in the management of patients with acute cerebrovascular events and prevent poor outcome and mortality. The purpose of this review is to provide an overview of the development of potential biomarkers of brain damage to increase diagnostic possibilities. For this purpose, we searched the PubMed database of studies on the diagnostic potential of brain injury biomarkers. We also accessed information from Clinicaltrials.gov to identify any clinical trials of biomarker measurements for the diagnosis of brain damage. In total, we present 41 proteins, enzymes and hormones that have been considered as biomarkers for brain injury, of which 20 have been studied in clinical trials. Several microRNAs have also emerged as potential clinical biomarkers for early diagnosis. Combining multiple biomarkers in a panel, along with other parameters, is yielding promising outcomes.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Sarcopenia is a syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength, which is commonly associated with NAFLD. Adenosine-to-inosine editing, catalysed by adenosine deaminase acting on RNA (ADAR), is an important post-transcriptional modification of genome-encoded RNA transcripts. Three ADAR gene family members, including ADAR1, ADAR2 and ADAR3, have been identified. However, the functional role of ADAR2 in obesity-associated NAFLD and sarcopenia remains unclear.

ADAR2+/+/GluR-BR/R mice (wild type [WT]) and ADAR2-/-/GluR-BR/R mice (ADAR2 knockout [KO]) were subjected to feeding with standard chow or high-fat diet (HFD) for 20 weeks at the age of 5 weeks. The metabolic parameters, hepatic lipid droplet, grip strength test, rotarod test, muscle weight, fibre cross-sectional area (CSA), fibre types and protein associated with protein degradation were examined. Systemic and local tissues serum amyloid A1 (SAA1) were measured. The effects of SAA1 on C2C12 myotube atrophy were investigated.

ADAR2 KO mice fed with HFD exhibited lower body weight (-7.7%, P < 0.05), lower liver tissue weight (-20%, P < 0.05), reduced liver lipid droplets in concert with a decrease in hepatic triglyceride content (-24%, P < 0.001) and liver injury (P < 0.01). ADAR2 KO mice displayed protection against HFD-induced glucose intolerance, insulin resistance and dyslipidaemia. Skeletal muscle mass (P < 0.01), muscle strength (P < 0.05), muscle endurance (P < 0.001) and fibre size (CSA; P < 0.0001) were improved in ADAR2 KO mice fed with HFD compared with WT mice fed with HFD. Muscle atrophy-associated transcripts, such as forkhead box protein O1, muscle atrophy F-box/atrogin-1 and muscle RING finger 1/tripartite motif-containing 63, were decreased in ADAR2 KO mice fed with HFD compared with WT mice fed with HFD. ADAR2 deficiency attenuates HFD-induced local liver and skeletal muscle tissue inflammation. ADAR2 deficiency abolished HFD-induced systemic (P < 0.01), hepatic (P < 0.0001) and muscular (P < 0.001) SAA1 levels. C2C12 myotubes treated with recombinant SAA1 displayed a decrease in myotube length (-37%, P < 0.001), diameter (-20%, P < 0.01), number (-39%, P < 0.001) and fusion index (-46%, P < 0.01). Myogenic markers (myosin heavy chain and myogenin) were decreased in SAA1-treated myoblast C2C12 cells.

These results provide novel evidence that ADAR2 deficiency may be important in obesity-associated sarcopenia and NAFLD. Increased SAA1 might be involved as a regulatory factor in developing sarcopenia in NAFLD.

The lactoferrin (LTF) gene behaves like a tumor suppressor gene in diverse tumors, such as renal cancer, nasopharyngeal carcinoma and gastric cancer. However, the prognostic value of LTF expression in patients with glioblastoma remains unclear. In this study, the expression levels of LTF in patients with GBM were investigated in TCGA, GEPIA, CGGA and GEO database, and a survival analysis of LTF based on TCGA and CGGA was performed. Furthermore, the present study demonstrated the LTF gene co-expression, PPI network, KEGG/GO enrichment and immune cell infiltration analysis on TCGA and TIMER2.0 database. We found that LTF expression was significantly upregulated in GBM samples compared with normal samples and other glioma samples, and Kaplan-Meier analysis demonstrated that the overexpression of LTF were significantly associated with worse overall survival (OS) and 5-year OS in GBM patients (P < 0.05). KEGG/GO enrichment analysis demonstrated that functions of LTF concentrated in immune and inflammatory response and peptidase regulation (P < 0.05). Immune cell infiltration analysis presented that high LTF expression exhibited dysregulated immune infiltration (i.e., CD4 + T cells, neutrophils, macrophages, myeloid dendritic cells and cancer associated fibroblast). LTF was upregulated in tumors and correlated with worse OS in GBM patients, and LTF might function as an oncogene via inducing dysregulated immune infiltration in GBM.

Crohn's disease (CD) is a chronic inflammatory disease that most frequently affects part of the distal ileum, but it may affect any part of the gastrointestinal tract. CD may also be related to systemic inflammation and extraintestinal manifestations. Alzheimer's disease (AD) is the most common neurodegenerative disease, gradually worsening behavioral and cognitive functions. Despite the meaningful progress, both diseases are still incurable and have a not fully explained, heterogeneous pathomechanism that includes immunological, microbiological, genetic, and environmental factors. Recently, emerging evidence indicates that chronic inflammatory condition corresponds to an increased risk of neurodegenerative diseases, and intestinal inflammation, including CD, increases the risk of AD. Even though it is now known that CD increases the risk of AD, the exact pathways connecting these two seemingly unrelated diseases remain still unclear. One of the key postulates is the gut-brain axis. There is increasing evidence that the gut microbiota with its proteins, DNA, and metabolites influence several processes related to the etiology of AD, including β-amyloid abnormality, Tau phosphorylation, and neuroinflammation. Considering the role of microbiota in both CD and AD pathology, in this review, we want to shed light on bacterial amyloids and their potential to influence cerebral amyloid aggregation and neuroinflammation and provide an overview of the current literature on amyloids as a potential linker between AD and CD.

Ovarian cancer, marked by high rate of recurrence, novel therapeutic strategies are needed to improve patient outcome. One of the potential strategies is inducing ferroptosis in ovarian cancer cells. Ferroptosis is an iron-dependent, lipid peroxidation-driven mode of cell death primarily occurring on the cell membrane. PTRF, an integral component of the caveolae structures located on the cell membrane, is involved in a multitude of physiological processes, including but not limited to, endocytosis, signal transduction, and lipid metabolism. This study elucidates the relationship between PTRF and ferroptosis in ovarian cancer, offering a fresh perspective for the development of new therapeutic strategies. We knocked down PTRF employing siRNA in the ovarian cancer cell lines HEY and SKOV3, following which we stimulated ferroptosis with Erastin (Era). Our research indicates that the lack of PTRF sensitizes cancer cells to ferroptosis, likely by altering membrane stability and tension, thereby affecting signal pathways related to ferroptosis, such as lipid and atherosclerosis, fluid shear stress, and atherosclerosis. Our findings provide new insights for developing new treatments for ovarian cancer.

Serum amyloid A (SAA) is a highly conserved acute-phase protein that plays roles in activating multiple pro-inflammatory pathways during the acute inflammatory response and is commonly used as a biomarker of inflammation. It has been linked to beneficial roles in tissue repair through improved clearance of lipids and cholesterol from sites of damage. In patients with chronic inflammatory diseases, elevated levels of SAA may contribute to increased severity of the underlying condition. The majority of circulating SAA is bound to lipoproteins, primarily high-density lipoprotein (HDL). Interaction with HDL not only stabilizes SAA but also alters its functional properties, likely through altered accessibility of protein-protein interaction sites on SAA. While high-resolution structures for lipid-free, or apo-, forms of SAA have been reported, their relationship with the HDL-bound form of the protein, and with other possible mechanisms of SAA binding to lipids, has not been established. Here, we have used multiple biophysical techniques, including SAXS, TEM, SEC-MALS, native gel electrophoresis, glutaraldehyde crosslinking, and trypsin digestion to characterize the lipid-free and lipid-bound forms of SAA. The SAXS and TEM data show the presence of soluble octamers of SAA with structural similarity to the ring-like structures reported for lipid-free ApoA-I. These SAA octamers represent a previously uncharacterized structure for lipid-free SAA and are capable of scaffolding lipid nanodiscs with similar morphology to those formed by ApoA-I. The SAA-lipid nanodiscs contain four SAA molecules and have similar exterior dimensions as the lipid-free SAA octamer, suggesting that relatively few conformational rearrangements may be required to allow SAA interactions with lipid-containing particles such as HDL. This study suggests a new model for SAA-lipid interactions and provides new insight into how SAA might stabilize protein-lipid nanodiscs or even replace ApoA-I as a scaffold for HDL particles during inflammation.

Serum amyloid A (SAA) predominantly synthesized by hepatocytes is a classical acute phase protein and has been extensively studied in mammals. However, the studies on the structure and properties of fish SAA are limited although SAA genes have been cloned and identified from various fishes. In the present study, a cDNA of grass carp (Ctenopharyngodon idella) SAA (gcSAA) was cloned and characterized, displaying a high homology with its counterparts in vertebrates. gcSAA mRNA was expressed with highest abundance in the liver and its levels were increased by a 24-hour infection of Aeromonas hydrophila (A. hydrophila) for more than 5 folds in the intestine, 15 folds in the spleen, 75 folds in the head kidney and 100 folds in the liver, implying that it is an acute phase protein in grass carp. Subsequently, recombinant gcSAA protein (rgcSAA) was prepared from a prokaryotic expression system after codon optimization of its coding sequence. The direct antibacterial activity assay and the plate count assay disclosed that gcSAA inhibited the growth and survival of A. hydrophila but not Edwardsiella piscicida (E. piscicida) which both are common bacterial pathogens in aquaculture. The propidium iodide (PI) uptake assay confirmed the bactericidal property of gcSAA, showing that it is able to enhance the uptake of PI in A. hydrophila but not E. piscicida. These findings revealed the molecular features of gcSAA and its roles in host defense against bacterial infection.

Renal amyloid-associated (AA) amyloidosis is a harmful complication of familial Mediterranean fever (FMF). Its occurrence involves polymorphisms and mutations in the Serum Amyloid A1 (SAA1) and Mediterranean Fever (MEFV) genes, respectively. In Algeria, the association between SAA1 variants and FMF-related amyloidosis was not investigated, hence the aim of this case-control study. It included 60 healthy controls and 60 unrelated FMF patients (39 with amyloidosis, and 21 without amyloidosis). All were genotyped for the SAA1 alleles (SAA1.1, SAA1.5, and SAA1.3), and a subset of them for the - 13 C/T polymorphism by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Comparisons between genotype and allele frequencies were performed using Chi-square and Fisher tests. The SAA1.1/1.1 genotype was predominant in amyloid FMF patients, compared to non-amyloid FMF patients (p = 0.001) and controls (p < 0.0001). SAA1.1/1.5 was higher in non-amyloid patients (p = 0.0069) and in controls (p = 0.0082) than in patients with amyloidosis. Bivariate logistic regression revealed an increased risk of AA amyloidosis with three genotypes, SAA1.1/1.1 [odds ratio 7.589 (OR); 95% confidence interval (CI): 2.130-27.041] (p = 0.0018), SAA1.1/1.3 [OR 5.700; 95% CI: 1.435-22.644] (p = 0.0134), and M694I/M694I [OR 4.6; 95% CI: 1.400-15.117] (p = 0.0119). The SAA1.1/1.5 genotype [OR 0.152; 95% CI: 0.040-0.587] (p = 0.0062) was protective against amyloidosis. In all groups, the - 13 C/C genotype predominated, and was not related to renal complication [OR 0.88; 95% CI: 0.07-10.43] (p = 0.915). In conclusion, in contrast to the - 13 C/T polymorphism, the SAA1.1/1.1, SAA1.1/1.3 and M694I/M694I genotypes may increase the risk of developing renal AA amyloidosis in the Algerian population.

Serum amyloid A1 (SAA1), an inflammation-related molecule, is associated with the malignant progression of many tumors. This study aimed to investigate the role of SAA1 in the progression of esophageal squamous cell carcinoma (ESCC) and its molecular mechanisms. The expression of SAA1 in ESCC tissues and cell lines was analyzed using bioinformatics analysis, western blotting, and reverse transcription-quantitative PCR (RT‒qPCR). SAA1-overexpressing or SAA1-knockdown ESCC cells were used to assess the effects of SAA1 on the proliferation, migration, apoptosis of cancer cells and the growth of xenograft tumors in nude mice. Western blotting, immunofluorescence and RT‒qPCR were used to investigate the relationship between SAA1 and β-catenin and SAA1 and sphingosine 1-phosphate (S1P)/sphingosine 1-phosphate receptor 1 (S1PR1). SAA1 was highly expressed in ESCC tissues and cell lines. Overexpression of SAA1 significantly promoted the proliferation, migration and the growth of tumors in nude mice. Knockdown of SAA1 had the opposite effects and promoted the apoptosis of ESCC cells. Moreover, SAA1 overexpression promoted the phosphorylation of β-catenin at Ser675 and increased the expression levels of the β-catenin target genes MYC and MMP9. Knockdown of SAA1 had the opposite effects. S1P/S1PR1 upregulated SAA1 expression and β-catenin phosphorylation at Ser675 in ESCC cells. In conclusion, SAA1 promotes the progression of ESCC by increasing β-catenin phosphorylation at Ser675, and the S1P/S1PR1 pathway plays an important role in its upstream regulation.

The response to programmed death-1 (PD-1) blockade varies in hepatocellular carcinoma (HCC). We utilize a panel of 16 serum factors to show that a circulating level of serum amyloid A (SAA) > 20.0 mg/L has the highest accuracy in predicting anti-PD-1 resistance in HCC. Further experiments show a correlation between peritumoral SAA expression and circulating SAA levels in patients with progressive disease after PD-1 inhibition. In vitro experiments demonstrate that SAA induces neutrophils to express PD-L1 through glycolytic activation via an LDHA/STAT3 pathway and to release oncostatin M, thereby attenuating cytotoxic T cell function. In vivo, genetic or pharmacological inhibition of STAT3 or SAA eliminates neutrophil-mediated immunosuppression and enhances antitumor efficacy of anti-PD-1 treatment. This study indicates that SAA may be a critical inflammatory cytokine implicated in anti-PD-1 resistance in HCC. Targeting SAA-induced PD-L1+ neutrophils through STAT3 or SAA inhibition may present a potential approach for overcoming anti-PD1 resistance.

We have previously reported that the gut microbiota of healthy infants harbors allergy-protective bacteria taxa that are depleted in infants with cow's milk allergy (CMA). Few reports have investigated the role of the gut microbiota in promoting allergic responses. In this study we selected a CMA-associated microbiota with increased abundance of Gram-negative bacteria for analysis of its proinflammatory potential. LPS is the major component of the outer membrane of Gram-negative bacteria. Colonization of mice with a global or conditional mutation of the LPS receptor TLR4 with this CMA microbiota induced expression of serum amyloid A1 (Saa1) and other Th17-, B cell-, and Th2-associated genes in the ileal epithelium in a TLR4-dependent manner. In agreement with the gene expression data, mice colonized with the CMA microbiota have expanded populations of Th17 and regulatory T cells and elevated concentrations of fecal IgA. Importantly, we used both antibiotic-treated specific pathogen-free and germ-free rederived mice with a conditional mutation of TLR4 in the CD11c+ compartment to demonstrate that the induction of proinflammatory genes, fecal IgA, and Th17 cells is dependent on TLR4 signaling. Furthermore, metagenomic sequencing revealed that the CMA microbiota has an increased abundance of LPS biosynthesis genes. Taken together, our results show that a microbiota displaying a higher abundance of LPS genes is associated with TLR4-dependent proinflammatory gene expression and a mixed type 2/type 3 response in mice, which may be characteristic of a subset of infants with CMA.

Metabolic dysfunction-associated steatotic liver disease (MASLD) which formerly known as non-alcoholic fatty liver disease (NAFLD) is one of the causes of liver cirrhosis. Currently, a growing number of liver cirrhosis cases develop on the basis of MASLD, and the pathogenesis of MASLD remains unclear. This paper reviews the research progress on the involvement of different metabolism-related signalling pathways in the pathogenesis and development of MASLD.

At present, although there are tumor markers for hepatocellular carcinoma (HCC), markers with better predictive efficiency are needed. SAA4 gene expression in liver tumor and paracancerous tissues was analyzed using The Cancer Genome Atlas database. The differentially expressed genes (DEGs) were analyzed and visualized by heatmap and volcano plot. Survival analysis was performed based on SAA4 expression. SAA4 expression was compared in patients grouped based on clinicopathological features, and gene set enrichment analysis (GSEA) was conducted. Immunohistochemical staining was used to verify the SAA4 protein staining intensity from The Human Protein Atlas database and our center's samples. The diagnostic value of SAA4 for HCC was evaluated by receiver operating characteristic curves. SAA4 was expressed at low levels in HCC tissues, and low SAA4 expression was associated with a poor prognosis in HCC. In addition, SAA4 expression decreased with HCC progression. There were 188 upregulated DEGs and 1551 downregulated DEGs between the high and low SAA4 expression groups. Complement and coagulation cascades, fatty acid metabolism, and ECM receptor interaction were significantly enriched in the GSEA. SAA4 had good predictive efficacy for HCC and even early HCC and was superior to AFP. In general, low SAA4 expression was associated with advanced HCC stage and a poor prognosis. In addition, SAA4 may be helpful for the diagnosis of early HCC and may become a novel tumor marker with good predictive power for HCC.

As the most prevalent primary brain tumor in adults, glioma accounts for the majority of all central nervous system malignant tumors. The concept of PANoptosis is a relatively new, underlining the interconnection and synergy among three distinct pathways: pyroptosis, apoptosis and necroptosis.

We performed single-cell annotations of glioma cells and determined crucial signaling pathways through cell chat analysis. Using least absolute shrinkage and selection operator (LASSO) and Cox analyses, we identified a gene set with prognostic values. Our model was validated using independent external cohort. In addition, we employed single-sample gene set enrichment analysis and xCell analyses to describe the detailed profile of infiltrated immune cells and depicted the gene mutation landscape in the two groups.

We identified seven distinct cell clusters in glioma samples, including oligodendrocyte precursor cells (OPCs), myeloid cells, tumor cells, oligodendrocytes, astrocytes, vascular cells and neuronal cells. We found that myeloid cells showed the highest PANoptosis activity. An intense mutual cell communication pattern between the tumor cells and OPCs and oligodendrocytes was observed. Differentially expressed genes between the high-PANoptosis and low-PANoptosis cell groups were obtained, which were enriched to actin cytoskeleton, cell adhesion molecules and gamma R-mediated phagocytosis pathways. We determined a set of five genes of prognostic significance: SAA1, SLPI, DCX, S100A8 and TNR. The prognostic differences between the two groups in the internal and external sets were found to be statistically significant. We found a marked correlation between S100A8 and activated dendritic cell, macrophage, mast cell, myeloid derived suppressor cell and Treg infiltration. Moreover, we have observed a significant increase of PTEN mutation in the high risk (HR) group of glioma patients.

In the present study, we have constructed a prognostic model that is based on the PANoptosis, and we have demonstrated its significant efficacy in stratifying patients with glioma. This innovative prognostic model offers novel insights into precision immune treatments that could be used to combat this disease and improve patient outcomes, thereby providing a new avenue for personalized treatment options.