Regulation of CNS pathology by Serpina3n/SERPINA3: The knowns and the puzzles.

Neuroinflammation, blood-brain barrier (BBB) dysfunction, neuron and glia injury/death and myelin damage are common central nervous system (CNS) pathologies observed in various neurological diseases and injuries. Serine protease inhibitor (Serpin) clade A member 3n (Serpina3n), and its human orthologue SERPINA3, is an acute-phase inflammatory glycoprotein secreted primarily by the liver into the bloodstream in response to systemic inflammation. Clinically, SERPINA3 is dysregulated in brain cells, cerebrospinal fluid and plasma in various neurological conditions. Although it has been widely accepted that Serpina3n/SERPINA3 is a reliable biomarker of reactive astrocytes in diseased CNS, recent data have challenged this well-cited concept, suggesting instead that oligodendrocytes and neurons are the primary sources of Serpina3n/SERPINA3. The debate continues regarding whether Serpina3n/SERPINA3 induction represents a pathogenic or a protective mechanism. Here, we propose possible interpretations for previously controversial data and present perspectives regarding the potential role of Serpina3n/SERPINA3 in CNS pathologies, including demyelinating disorders where oligodendrocytes are the primary targets. We hypothesise that the 'good' or 'bad' aspects of Serpina3n/SERPINA3 depend on its cellular sources, its subcellular distribution (or mis-localisation) and/or disease/injury types. Furthermore, circulating Serpina3n/SERPINA3 may cross the BBB to impact CNS pathologies. Cell-specific genetic tools are critically important to tease out the potential roles of cell type-dependent Serpina3n in CNS diseases/injuries.

Potential diagnostic markers shared between non-alcoholic fatty liver disease and atherosclerosis determined by machine learning and bioinformatic analysis.

Background: Evidence indicates that chronic non-alcoholic fatty liver disease (NAFLD) can increase the risk of atherosclerosis (AS), but the underlying mechanism remains unclear. Objective: This study is intended for confirming key genes shared between NAFLD and AS, and their clinical diagnostic value to establish a foundation for searching novel therapeutic targets. Methods: We downloaded the Gene Expression Omnibus (GEO) datasets, GSE48452 and GSE89632 for NAFLD and GSE100927, GSE40231 and GSE28829 for AS. The progression of NAFLD co-expression gene modules were recognized via weighted gene co-expression network analysis (WGCNA). We screened for differentially expressed genes (DEGs) associated with AS and identified common genes associated with NAFLD and AS using Venn diagrams. We investigated the most significant core genes between NAFLD and AS using machine learning algorithms. We then constructed a diagnostic model by creating a nomogram and evaluating its performance using ROC curves. Furthermore, the CIBERSORT algorithm was utilized to explore the immune cell infiltration between the two diseases, and evaluate the relationship between diagnostic genes and immune cells. Results: The WGCNA findings associated 1,129 key genes with NAFLD, and the difference analysis results identified 625 DEGs in AS, and 47 genes that were common to both diseases. We screened the core RPS6KA1 and SERPINA3 genes associated with NAFLD and AS using three machine learning algorithms. A nomogram and ROC curves demonstrated that these genes had great clinical meaning. We found differential expression of RPS6KA1 in patients with steatosis and NASH, and of SERPINA3 only in those with NASH compared with normal individuals. Immune infiltration findings revealed that macrophage and mast cell infiltration play important roles in the development of NAFLD and AS. Notably, SERPINA3 correlated negatively, whereas RPS6KA1 correlated positively with macrophages and mast cells. Conclusion: We identified RPS6KA1 and SERPINA3 as potential diagnostic markers for NAFLD and AS. The most promising marker for a diagnosis of NAFLD and AS might be RPS6KA1, whereas SERPINA3 is the most closely related gene for NASH and AS. We believe that further exploration of these core genes will reveal the etiology and a pathological relationship between NAFLD and AS.

Steroid inhibited Serpina3n expression which was positively correlated with the degrees of spinal cord injury.

Aims: The aim of our project was to identify proteins associated with the extent of spinal cord injury (SCI) and subsequent long-term neurological recovery. Methods: Through proteomic analysis, we identified proteins that are differentially expressed specifically in the acute phase of injury. We analyzed the concentrations of differentially expressed proteins in serum and the injured spinal cord segment by ELISA. Results: Serpina3n protein expression in the injured spinal cord segment was increased 101-fold at 12 h after severe SCI and 89-fold at 12 h after mild SCI, as determined by LC‒MS/MS. In the mild and severe SCI groups, serum Serpina3n levels began to increase at 12 h and peaked at 24 h. At 12 h, 24 h and 3 d after injury, serum Serpina3n protein levels were significantly correlated with the severity of injury (12 h: r = 0.6034, P = 0.008; 24 h: r = 0.7542, P = 0.0003; 3 d: r = 0.862, P < 0.001). Serum Serpina3n levels at 2 h, 24 h and 3 d post injury were significantly correlated with long-term neurological recovery at 28 d after SCI (2 h: r = -0.5781, P = 0.012; 24 h: r = -0.5912, P = 0.0098; 3 d: r = -0.7792, P < 0.0001). Methylprednisolone treatment would decrease the serum Serpina3n levels in mice with mild and severe SCI compared with those in placebo-group mice at 12 h and 24 h after SCI. The serum Serpina3n concentration in the severe SCI group was significantly reduced on the third day after steroid treatment. Conclusion: Taken together, these data suggest that serpina3n may be a circulating biomarker of acute SCI and may be closely associated with injury severity and long-term motor function recovery.

Cellular architecture of evolving neuroinflammatory lesions and multiple sclerosis pathology.

Multiple sclerosis (MS) is a neurological disease characterized by multifocal lesions and smoldering pathology. Although single-cell analyses provided insights into cytopathology, evolving cellular processes underlying MS remain poorly understood. We investigated the cellular dynamics of MS by modeling temporal and regional rates of disease progression in mouse experimental autoimmune encephalomyelitis (EAE). By performing single-cell spatial expression profiling using in situ sequencing (ISS), we annotated disease neighborhoods and found centrifugal evolution of active lesions. We demonstrated that disease-associated (DA)-glia arise independently of lesions and are dynamically induced and resolved over the disease course. Single-cell spatial mapping of human archival MS spinal cords confirmed the differential distribution of homeostatic and DA-glia, enabled deconvolution of active and inactive lesions into sub-compartments, and identified new lesion areas. By establishing a spatial resource of mouse and human MS neuropathology at a single-cell resolution, our study unveils the intricate cellular dynamics underlying MS.

Proteomic analysis of multiple organ dysfunction induced by rhabdomyolysis.

Rhabdomyolysis (RM) leads to dysfunction in the core organs of kidney, lung and heart, which is an important reason for the high mortality and disability rate of this disease. However, there is a lack of systematic research on the characteristics of rhabdomyolysis-induced injury in various organs and the underlying pathogenetic mechanisms, and especially the interaction between organs. We established a rhabdomyolysis model, observed the structural and functional changes in kidney, heart, and lung. It is observed that rhabdomyolysis results in significant damage in kidney, lung and heart of rats, among which the pathological damage of kidney and lung was significant, and of heart was relatively light. Meanwhile, we analyzed the differentially expressed proteins (DEPs) in the kidney, heart and lung between the RM group and the sham group based on liquid chromatography-tandem mass spectrometry (LC-MS/MS). In our study, Serpina3n was significantly up-regulated in the kidney, heart and lung. Serpina3n is a secreted protein and specifically inhibits a variety of proteases and participates in multiple physiological processes such as complement activation, inflammatory responses, apoptosis pathways, and extracellular matrix metabolism. It is inferred that Serpina3n may play an important role in multiple organ damage caused by rhabdomyolysis and could be used as a potential biomarker. This study comprehensively describes the functional and structural changes of kidney, heart and lung in rats after rhabdomyolysis, analyzes the DEPs of kidney, heart and lung, and determines the key role of Serpina3n in multiple organ injury caused by rhabdomyolysis. SIGNIFICANCE: This study comprehensively describes the functional and structural changes of kidney, heart and lung in rats after rhabdomyolysis, analyzes the DEPs of kidney, heart and lung, and determines the key role of Serpina3n in multiple organ injury caused by rhabdomyolysis.

SerpinA3N Regulates the Secretory Phenotype of Mouse Senescent Astrocytes Contributing to Neurodegeneration.

Senescent astrocyte accumulation in the brain during normal aging is a driver of age-related neurodegenerative diseases such as Alzheimer's disease. However, the molecular events underlying astrocyte senescence in Alzheimer's disease are not fully understood. In this study, we demonstrated that senescent astrocytes display a secretory phenotype known as the senescence-associated secretory phenotype (SASP), which is associated with the upregulation of various proinflammatory factors and the downregulation of neurotrophic growth factors (eg, NGF and BDNF), resulting in a decrease in astrocyte-mediated neuroprotection and increased risk of neurodegeneration. We found that SerpinA3N is upregulated in senescent primary mouse astrocytes after serial passaging in vitro or by H2O2 treatment. Further exploration of the underlying mechanism revealed that SerpinA3N deficiency protects against senescent astrocyte-induced neurodegeneration by suppressing SASP-related factors and inducing neurotrophic growth factors. Brain tissues from Alzheimer's disease model mice possessed increased numbers of senescent astrocytes. Moreover, senescent astrocytes exhibited upregulated SerpinA3N expression in vitro and in vivo, confirming that our cell model recapitulated the in vivo pathology of these neurodegenerative diseases. Altogether, our study reveals a novel molecular strategy to regulate the secretory phenotype of senescent astrocytes and implies that SerpinA3N and its regulatory mechanisms may be potential targets for delaying brain aging and aging-related neurodegenerative diseases.

Immunohistochemical Expression of the SERPINA3 Protein in Uterine Fibroids.

BACKGROUND: SERPINA3 (α-1-antichymotrypsin, AACT, ACT) is produced by the liver and released into plasma in an anti-inflammatory response and plays a role as a modulator of extracellular matrix (ECM) by inhibiting serine proteases. Numerous studies proved an increased level of SERPINA3 in many types of cancer, which could be linked to SERPINA3's anti-apoptotic function. AIM: In the context of progressive ECM fibrosis during the development of uterine fibroids, which are one of the most common hypertrophic changes within the uterus, it is interesting to describe the level of SERPINA3 protein in this type of lesion and the surrounding tissues. METHODS: We used immunohistochemical staining of the SERPINA3 protein and compared the intensity of the signal between the myoma tissue and the surrounding normal tissue. RESULTS: We showed a surprising reduction in the amount of the SERPINA3 protein within uterine fibroids compared to surrounding tissues. CONCLUSION: This observation sheds new light on the role of this protein in the formation of proliferative changes and suggests that understanding the mechanism of its action may become the basis for the development of new diagnostic and therapeutic tools.

LAMB3 Promotes Intestinal Inflammation Through SERPINA3 and Is Directly Transcriptionally Regulated by P65 in Inflammatory Bowel Disease.

BACKGROUND: Various extracellular matrix (ECM) reshaping events are involved in inflammatory bowel disease (IBD). LAMB3 is a vital subunit of laminin-332, an important ECM component. Data on the biological function of LAMB3 in intestinal inflammation are lacking. Our aim is to discuss the effect of LAMB3 in IBD. METHODS: LAMB3 expression was assessed in cultured intestinal epithelial cells, inflamed mucosal tissues of patients and mouse colitis models. RNA sequencing, quantitative real-time polymerase chain reaction and Western blotting were used to detect the LAMB3 expression distribution and potential downstream target genes. Dual-luciferase assays and chromatin immunoprecipitation-quantitative polymerase chain reaction were used to determine whether P65 could transcriptionally activate LAMB3 under tumor necrosis factor α stimulation. RESULTS: LAMB3 expression was increased in inflammatory states in intestinal epithelial cells and colonoids and was associated with adverse clinical outcomes in Crohn's disease. Knockdown of LAMB3 inhibited the expression of proinflammatory cytokines. Mechanistically, LAMB3 expression was directly transcriptionally activated by P65 and was inhibited by nuclear factor kappa B inhibitors under tumor necrosis factor α stimulation. Furthermore, RNA sequencing and replenishment experiments revealed that LAMB3 upregulated SERPINA3 to promote intestinal inflammation via the integrin α3ß1/FAK pathway. CONCLUSION: We propose that LAMB3 could serve as a potential therapeutic target of IBD and a predictor of intestinal stenosis of Crohn's disease. Our findings demonstrate the important role of ECM in the progression of IBD and offer an experimental basis for the treatment and prognosis of IBD.

SERPINA3: A novel inflammatory biomarker associated with cerebral small vessel disease burden in ischemic stroke.

BACKGROUND AND OBJECTIVE: Inflammation has emerged as a prominent risk factor for cerebral small vessel disease (CSVD). However, the specific association between various inflammatory biomarkers and the development of CSVD remains unclear. Serine proteinase inhibitor A3 (SERPINA3), Matrix metalloproteinase-9 (MMP-9), Tissue inhibitor metalloproteinase-1 (TIMP-1), Monocyte Chemoattractant Protein-1 (MCP-1) are several inflammatory biomarkers that are potentially involved in the development of CSVD. In this present study, we aimed to investigate the relationship between candidate molecules and CSVD features. METHOD: The concentration of each biomarker was measured in 79 acute ischemic stroke patients admitted within 72 h after symptom onset. The associations between blood levels of inflammatory markers and CSVD score were investigated, as well as each CSVD feature, including white matter hyperintensities (WMH), lacunes, and enlarged perivascular spaces (EPVS). RESULTS: The mean age was 69.0 ± 11.8 years, and 65.8% of participants were male. Higher SERPINA3 level (>78.90 ng/mL) was significantly associated with larger WMH volume and higher scores on Fazekas's scale in all three models. Multiple regression analyses revealed the linear association between absolute WMH burden and SERPINA3 level, especially in model 3 (ß = 0.14; 95% confidence interval [CI], 0.04-0.24 ; p = 0.008 ). Restricted cubic spline regression demonstrated a dose-response relationship between SERPINA3 level and larger WMH volume (p nonlineariy = 0.0366 and 0.0378 in model 2 and mode 3, respectively). Using a receiving operating characteristic (ROC) curve, plasma SERPINA3 level of 64.15 ng/mL distinguished WMH >7.8 mL with the highest sensitivity and specificity (75.92% and 60%, respectively, area under curve [AUC] = 0.668, p = 0.0102). No statistically significant relationship has been found between other candidate biomarkers and CSVD features. CONCLUSION: In summary, among four inflammatory biomarkers that we investigated, SERPINA3 level at baseline was associated with WMH severity, which revealed a novel biomarker for CSVD and validated its relationship with inflammation and endothelial dysfunction.

CTSC promoted the migration and invasion of glioma cells via activation of STAT3/SERPINA3 axis.

Cathepsin C (CTSC) has been reported to be upregulated in several cancers, however, there are still many missing links about the role of CTSC in glioma. To address this knowledge gap, the present study employed bioinformatics analysis, Transwell assay, RT-qPCR and Western blot assays to investigate the expression level of CTSC in glioma tissues, its relationship with survival period, and its effect on the migration and invasion ability of glioma cells. The findings revealed that CTSC was upregulated in glioma and was associated with poor prognosis. Moreover, CTSC was found to promote cell migration and invasion abilities as well as epithelial-mesenchymal transition (EMT). A further study found that CTSC induced SERPINA3 and STAT3 expression in glioma cells. Additionally, we demonstrated that STAT3 signaling mediated upregulation of SERPINA3 expression by CTSC. In sum, our findings suggest that CTSC activates the STAT3/SERPINA3 axis to promote migration and invasion of glioma cells, which may lead to new potential therapeutic approaches for humans with cancer.

Hypothermic machine perfusion reduces donation after circulatory death liver ischemia-reperfusion injury through the SERPINA3-mediated PI3Kδ/Akt pathway.

Hypothermic machine perfusion (HMP) has been demonstrated to be more effective in mitigating ischemia-reperfusion injury (IRI) of donation after circulatory death (DCD) organs than cold storage (CS), yet the underlying mechanism remains obscure. We aimed to propose a novel therapeutic approach to ameliorate IRI in DCD liver transplantation. Twelve clinical liver samples were randomly assigned to HMP or CS treatment and subsequent transcriptomics analysis was performed. By combining in vivo HMP models, we discovered that HMP attenuated inflammation, oxidative stress, and apoptosis in DCD liver through a SEPRINA3-mediated PI3Kδ/AKT signaling cascade. Moreover, in the hypoxia/reoxygenation (H/R) model of BRL-3A, overexpression of SERPINA3 mitigated H/R-induced apoptosis, while SERPINA3 knockdown exacerbated cell injury. Idelalisib (IDE) treatment also reversed the protective effect of SERPINA3 overexpression. Overall, our research provided new insights into therapeutic strategies and identified potential novel molecular targets for therapeutic intervention against DCD liver.

Unveiling the role of miR-137-3p/miR-296-5p/SERPINA3 signaling in colorectal cancer progression: integrative analysis of gene expression profiles and in vitro studies.

BACKGROUND: Colorectal cancer (CRC) is a prevalent malignancy worldwide, with increasing incidence and mortality rates. Although treatment options have improved, CRC remains a leading cause of death due to metastasis. Early intervention can significantly improve patient outcomes, making it crucial to understand the molecular mechanisms underlying CRC metastasis. In this study, we performed bioinformatics analysis to identify potential genes associated with CRC metastasis. METHODS: We downloaded and integrated gene expression datasets (GSE89393, GSE100243, and GSE144259) from GEO database. Differential expression analysis was conducted, followed by Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The hub gene SERPINA3 was selected for further in vitro functional studies. Additionally, the role of miR-137-3p/miR-296-5p/ Serpin family A member 3 (SERPINA3) in CRC cell function was investigated using in vitro assays. RESULTS: Analysis of the gene expression datasets revealed differentially expressed genes (DEGs) associated with CRC metastasis. GO analysis showed enrichment in biological processes such as blood coagulation regulation and wound healing. Cellular component analysis highlighted extracellular matrix components and secretory granules. Molecular function analysis identified activities such as serine-type endopeptidase inhibition and lipoprotein receptor binding. KEGG analysis revealed involvement in pathways related to complement and coagulation cascades, cholesterol metabolism, and immune responses. The common DEGs among the datasets were further investigated. We identified SERPINA3 as a hub gene associated with CRC metastasis. SERPINA3 exerted enhanced effects on migration, proliferation and epithelial-mesenchymal transition (EMT) and inhibitory effects on caspase-3/-9 activities in HT29 and SW620 cells. MiR-137-3p overexpression increased activities of caspase-3/-9, decreased migration and proliferation, and also repressed EMT in HT29 cells, which were obviously attenuated by SERPINA3 enforced overexpression. Consistently, SERPINA3 enforced overexpression also largely reversed miR-296-5p mimics-induced increased in activities of caspase-3/-9, decrease in migration, proliferation and EMT in HT29 cells. CONCLUSION: Through bioinformatics analysis, we identified potential genes associated with CRC metastasis. The functional studies focusing on SERPINA3/miR-137-3p/miR-296-5p further consolidated its role in regulating CRC progression. Our findings provide insights into novel mechanisms underlying CRC metastasis and might contribute to the development of effective treatment strategies. However, the role of SERPINA3/miR-137-3p/miR-296-5p signaling in CRC still requires further investigation.

SerpinA3 Promotes Myocardial Infarction in Rat and Cell-based Models.

This study aimed to examine the role and molecular mechanism of the nuclear factor κB (NFκB)/serine protease inhibitor A3 (SerpinA3) interaction in myocardial ischemia-reperfusion (IR) injury. First, a rat model for myocardial ischemia-reperfusion injury was established, using 2,3,5-triphenyltetrazolium chloride to measure the size of the myocardial infarction. Pathological variations in myocardial tissue were detected using hematoxylin-eosin staining. Flow cytometry and terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) staining were used to measure cell death in the rat model. The SerpinA3 mRNA and protein expressions in the myocardium of IR-model rats were remarkably higher than those in the control group. Furthermore, the oxidative, inflammatory, and apoptotic activities of the myocardial tissue of SerpinA3-knockdown (KD) rats were significantly improved compared to those in the WT group. SerpinA3-KD also contributed to the recovery of cardiac function in IR-model rats. Additionally, silencing of SerpinA3 inhibited p65 phosphorylation in myocardial tissues and reduced H2O2-induced inflammation, oxidative stress, and apoptosis in myocardial cells. The expression of SerpinA3 increased in myocardial tissue after IR stimulation. Knockdown of SerpinA3 can deactivate NF-κB and reduce inflammation, oxidative stress, and apoptosis in vivo and in vitro, thereby lessening myocardial injury caused by IR. In conclusion, SerpinA3 promotes myocardial infarction in rat and cell-based models by activating NF-κB. However, the mechanism by which increased Serpina3 expression causes downstream NF-κB activation to mediate the proposed, pathological effects in myocardial IR injury remain untested and worthy of future investigations.

Serpina3n/serpina3 alleviates cyclophosphamide-induced interstitial cystitis by activating the Wnt/ß-catenin signal.

BACKGROUND/OBJECTIVE: Serpina3n/Serpina3 has been identified to be implicated in inflammatory diseases, but its role in interstitial cystitis/bladder pain syndrome (IC/BPS) remains unknown. Here, we aimed to reveal serpina3n/serpina3 role in IC/BPS in vivo and in vitro. METHODS: The IC/BPS model in mice was induced by intraperitoneal injection of 150 mg/kg of cyclophosphamide (CYP). HE and toluidine blue staining were used for histology assessment. Serpina3n/serpina3 expression in the bladder tissues from IC/BPS patients and mouse models were determined by qPCR, immunohistochemistry and western blotting. XAV-939 treatment was applied to inhibit ß-catenin activation. Serpina3 role in modulating the growth and apoptosis of HBlEpCs, a human primary bladder epithelial cell line, was assessed by CCK-8 and flow cytometry assays. RESULTS: Serpina3n/serpina3 expression was decreased in both human and mice bladder tissues with IC/BPS. Upregulation of serpina3n significantly alleviated CYP-induced bladder injury, with decreased mast cells and pro-inflammatory factor levels, including IL-1ß, IL-6, and TNF-α, while increased IL-10 level. In addition, serpina3 overexpression inhibited the apoptosis of HBlEpCs, and increased cell growth. In mechanism, we found that serpina3 overexpression promoted the activation of wnt/ß-catenin signaling. And, the inhibition of wnt/ß-catenin signaling with XAV-939 abolished serpina3n/serpina3 role in protecting bladder tissues from CYP-induced cystitis, as well as inhibiting HBlEpC apoptosis. CONCLUSION: Serpina3n/serpina3 expression was decreased in IC/BPS. Overexpression of serpina3n could alleviate CYP-induced IC/BPS by activating the Wnt/ß-catenin signal. This study may provide a new therapeutic strategy for IC/BPS.

Overexpression of SERPINA3 suppresses tumor progression by modulating SPOP/NF­κB in lung cancer.

The pathogenesis mechanism of lung cancer is very complex, with high incidence and mortality. Serpin family A member 3 (SERPINA3) expression levels were reduced in the sera of patients with lung cancer and may be a candidate diagnostic and prognostic survival biomarker in lung cancer, as previously reported. However, the detailed biological functions of SERPINA3 in the pathogenesis of lung cancer remain unknown. In the present study, it was aimed to explore the effects of SERPINA3 on the occurrence of lung cancer. SERPINA3 expression was assessed using bioinformatics database analysis and experimental detection. Then, the biological effects of SERPINA3 were investigated in a cell culture system and a xenograft model of human lung cancer. The potential regulatory mechanism of SERPINA3 in lung cancer was explored by data­independent acquisition mass spectrometry (DIA­MS) detection and further validated by western blotting (WB). The results indicated that SERPINA3 expression levels were significantly downregulated in lung cancer tissues and cell lines. At the cellular level, it was revealed that overexpressed SERPINA3 inhibited cell growth, proliferation, migration and invasion and promoted the apoptosis of lung cancer cells. Moreover, overexpressed SERPINA3 enhanced the sensitivity of lung cancer cells to osimertinib. In vivo, a xenograft model of human lung cancer was established with BALB/c nude mice. After the injection of A549 cells, the tumor growth of the tumor­bearing mice in the SERPINA3­overexpressing group increased more slowly, and the tumor volume was smaller than that in the empty­vector group. Mechanistically, a total of 65 differentially expressed proteins were identified. It was found that the speckle­type POZ protein (SPOP) was significantly upregulated in SERPINA3­overexpressing H157 cells using DIA­MS detection and analysis. WB validation showed that SPOP expression increased, and NF­kappaB (NF­κB) p65 was inhibited in cell lines and tumor tissues of mice when SERPINA3 was overexpressed. The present findings suggest that SERPINA3 is involved in the development of lung cancer and has an antineoplastic role in lung cancer.

Osteoblast-derived extracellular vesicles exert osteoblastic and tumor-suppressive functions via SERPINA3 and LCN2 in prostate cancer.

Clinically, the osteolytic phenotype is rare in prostate cancer (PCa), and the prognosis is generally worse than that of the osteoblastic phenotype. Osteoblastic prostate cancer (BPCa) is a major type of bone metastasis. Several factors responsible for osteogenesis have been identified, but the molecular mechanism of osteoblastic bone metastasis in PCa is not fully understood. Here, we show the osteogenic and tumor-suppressive roles of SERPINA3 and LCN2 in BPCa. In a co-culture of osteoblasts (OBs) and BPCa cells, SERPINA3 and LCN2 were remarkably upregulated in BPCa via OB-derived extracellular vesicles, while they were not in the co-culture of OBs and osteolytic prostate cancer (LPCa) cells. In both the co-culture system and mouse xenograft experiments with intracaudal injection, enhanced expression of SERPINA3 and LCN2 in PCa led to osteogenesis. Additionally, the addition of SERPINA3 and LCN2 to BPCa cells significantly suppressed the proliferative potential. Retrospective analysis also confirmed that high expression levels of SERPINA3 and LCN2 were significantly correlated with a better prognosis. Our results may partially explain how osteoblastic bone metastasis develops and why the prognosis for BPCa is relatively better than that for LPCa.

Astrocyte-derived SerpinA3N promotes neuroinflammation and epileptic seizures by activating the NF-κB signaling pathway in mice with temporal lobe epilepsy.

Impaired activation and regulation of the extinction of inflammatory cells and molecules in injured neuronal tissues are key factors in the development of epilepsy. SerpinA3N is mainly associated with the acute phase response and inflammatory response. In our current study, transcriptomics analysis, proteomics analysis, and Western blotting showed that the expression level of Serpin clade A member 3N (SerpinA3N) is significantly increased in the hippocampus of mice with kainic acid (KA)-induced temporal lobe epilepsy, and this molecule is mainly expressed in astrocytes. Notably, in vivo studies using gain- and loss-of-function approaches revealed that SerpinA3N in astrocytes promoted the release of proinflammatory factors and aggravated seizures. Mechanistically, RNA sequencing and Western blotting showed that SerpinA3N promoted KA-induced neuroinflammation by activating the NF-κB signaling pathway. In addition, co-immunoprecipitation revealed that SerpinA3N interacts with ryanodine receptor type 2 (RYR2) and promotes RYR2 phosphorylation. Overall, our study reveals a novel SerpinA3N-mediated mechanism in seizure-induced neuroinflammation and provides a new target for developing neuroinflammation-based strategies to reduce seizure-induced brain injury.

Genetics of Generalized Pustular Psoriasis: Current Understanding and Implications for Future Therapeutics.

Psoriasis is a chronic inflammatory skin disease characterized by the appearance of clearly demarcated erythematous and scaly plaques. It can be divided into various types, including plaque, nail, guttate, inverse, and pustular psoriasis. Plaque psoriasis is the most commonly occurring type, though there is another rare but severe pustular autoinflammatory skin disease called generalized pustular psoriasis (GPP), which manifests with acute episodes of pustulation and systemic symptoms. Though the etiopathogenesis of psoriasis is not yet fully understood, a growing body of literature has demonstrated that both genetic and environmental factors play a role. The discovery of genetic mutations associated with GPP has shed light on our comprehension of the mechanisms of the disease, promoting the development of targeted therapies. This review will summarize genetic determinants as known and provide an update on the current and potential treatments for GPP. The pathogenesis and clinical presentation of the disease are also included for a comprehensive discussion.

Serpin-A3 is Associated with Persistent Albuminuria in Adolescents with Secondary Podocytopathy, in a Region with High Prevalence of Chronic Kidney Disease of Unknown Origin

Abstract Background: The state of Aguascalientes, Mexico, has been recognized as a chronic kidney disease hotspot. Screening studies have revealed a high prevalence of persistent albuminuria (pA), histologically characterized by glomerulomegaly, and incomplete podocyte fusion, probably associated with oligonephrony. To date, urinary biomarkers have not been explored in this population. Objective: The aim of the study was to identify the presence of potential biomarkers of early renal injury in patients with pA (pACR) and that correspond with the characteristic nephropathy profile that prevails in this entity. Methods: This is a cross-sectional, analytical, and comparative study. Four groups were recruited: adolescents aged 10-17 years with pACR, isolated albuminuria (iACR), no albuminuria (negative control), and adults with biopsy-confirmed glomerulopathy (positive control). Urinary excretion of SerpinA3, heat-shock protein-72 (HSP-72), podocalyxin (PCX), and nephrin was evaluated in urine samples. SerpinA3 and HSP-72 were analyzed by Western blot, and PCX and nephrin were quantified by enzyme-linked immunosorbent assay. Results: The mean GFR in the pACR group was 113.4 mL/min/1.73m2 and differed significantly only from that of the positive control group (65.1 mL/min/1.73m2). The mean albuminuria value in the pACR group was 48.9 mg/g. SerpinA3 concentration differed between groups (0.08 vs. 0.25 ng/mL, p < 0.001): it was significantly higher in the pACR group compared to the negative controls (p = 0.037). Conclusion: SerpinA3 was significantly associated with pA and could become a biomarker of early kidney injury. Further investigations are required to determine whether SerpinA3 precedes the development of albuminuria and its pathogenic role.

Sinapic acid and 3,3'-diindolylmethane potentiate cyclophosphamide antitumor activity through induction of apoptosis and inhibition of metastasis.

AIM: New therapeutic strategies are required to enhance the anticancer efficacy of chemotherapeutic drugs and to reduce their cytotoxicity. The purpose of this study was to assess the anti-tumor, antimetastatic and anti-apoptotic activities of sinapic acid (SA) and 3,3'-diindolylmethane (DIM) in solid Ehrlich carcinoma (SEC) induced in mice and combining SA or DIM compounds with cyclophosphamide (CYP). METHODS: For induction of solid tumor, the right hind limbs of mice were inoculated subcutaneously with Ehrlich carcinoma cells. After 5 days of tumor inoculation, mice were treated with SA (56 mg/kg), DIM (40 mg/kg), CYP (10 mg/kg), and their combinations (SA/CYP) and (SA/DIM) for 21 days. The mRNA levels of Elabela, Serpina3, caspase-3, MMP-2 and MMP-9 were assessed by qPCR. Tumor and liver tissues were stained with hematoxylin and eosin for histological examination. Serum was investigated for ALT and AST activities. MAIN FINDINGS: Treatment of SEC mice with SA and DIM significantly reduced solid tumor weight by 45.6% and 33.2%, respectively. They also reduced tumor size and increased life span of SEC mice. SA and DIM diminished area of metastatic nodules of tumor cells in the liver by 54.1% and 47.4%, respectively. They also reduced serum aminotransferases activities. Both SA and DIM were found to upregulate caspase 3 and downregulate MMP-2 and MMP-9. Furthermore, SA and DIM reduced gene expression of Elabela by (44.8% and 35.1%) and Serpina3 by (30.7% and 23.5%), respectively. SA and DIM were also shown to potentiate the anti-tumor activity CYP. SA and DIM showed promising antitumor effects and enhanced CYP antitumor activity mostly through upregulation of apoptotic caspase 3 and suppressing metastatic enzymes MMP-2 and MMP-9. Additionally, SA and DIM exhibited a hepatoprotective effect. Our results suggest that these natural compounds may be used to improve the efficacy and reduce the adverse effects of chemotherapeutic drugs in the treatment of solid malignancies.