Статті в журналах: "SERPINH1"

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Al-Khatib, Sohaib M., Ayah N. Al-Bzour, Mohammad N. Al-Majali, Laila M. Sa’d, Joud A. Alramadneh, Nour R. Othman, Abdel-Hameed Al-Mistarehi, and Safwan Alomari. "Exploring Genetic Determinants: A Comprehensive Analysis of Serpin B Family SNPs and Prognosis in Glioblastoma Multiforme Patients." Cancers 16, no. 6 (March 10, 2024): 1112. http://dx.doi.org/10.3390/cancers16061112.

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Serpins are serine proteinase inhibitors, with several serpins being overexpressed in cancer cells. Thus, we aim to analyze the single-nucleotide polymorphism (SNP) of Serpinb11 and its association with GBM survival. A cohort of 63 GBM patients recruited from King Abdullah University Hospital in Jordan underwent polymorphism analysis and overall survival (OS) assessments. The Cancer Genome Atlas (GBM) cohort was useful for validation. We constructed a risk score using the principal component analysis for the following Serpin genes: Serpinb3, Serpinb5, Serpinb6, Serpinb11, and Serpinb12, and patients were grouped into high- vs. low-risk groups based on the median cutoff. Univariable Cox models were used to study the survival outcomes. We identified a significant association between rs4940595 and survival. In the TCGA cohort, Serpinb3 alterations showed worse OS. Univariable Cox showed worse PFS outcomes with higher SERPINB5 and SERPINB6 expression. A Serpin B 5-gene risk score showed a trend towards worse PFS in the high-risk group. Upregulated DEGs showed GO enrichment in cytokine regulation and production, positive regulation of leukocyte activation, and the MAPK cascade. The high-risk group showed a significantly higher infiltration of M2 macrophages and activated mast cells. Our findings showed a significant role of the Serpin B family in GBM survival in the Jordanian population.

2

Jin, Xiao-Sheng, Lu-Xi Chen, Ting-Ting Ji, and Rong-Zhou Li. "SERPINH1 promoted the proliferation and metastasis of colorectal cancer by activating PI3K/Akt/mTOR signaling pathway." World Journal of Gastrointestinal Oncology 16, no. 5 (May 15, 2024): 1890–907. http://dx.doi.org/10.4251/wjgo.v16.i5.1890.

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BACKGROUND Serpin peptidase inhibitor clade H member 1 (SERPINH1) was initially recognized as an oncogene implicated in various human malignancies. Nevertheless, the clinical relevance and functional implications of SERPINH1 in colorectal cancer (CRC) remain largely elusive. AIM To investigate the effects of SERPINH1 on CRC cells and its specific mechanism. METHODS Quantitative real-time polymerase chain reaction, western blotting analysis, The Cancer Genome Atlas data mining and immunohistochemistry were employed to examine SERPINH1 expression in CRC cell lines and tissues. A series of in-vitro assays were performed to demonstrate the function of SERPINH1 and its possible mechanisms in CRC. RESULTS SERPINH1 demonstrated elevated expression levels in both CRC cells and tissues, manifested at both mRNA and protein tiers. Elevated SERPINH1 levels correlated closely with advanced T stage, lymph node involvement, and distant metastasis, exhibiting a significant association with poorer overall survival among CRC patients. Subsequent investigations unveiled that SERPINH1 overexpression notably bolstered CRC cell proliferation, invasion, and migration in vitro , while conversely, SERPINH1 knockdown elicited the opposite effects. Gene set enrichment analysis underscored a correlation between SERPINH1 upregulation and genes associated with cell cycle regulation. Our findings underscored the capacity of heightened SERPINH1 levels to expedite G1/S phase cell cycle progression via phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin pathway activation, thereby facilitating CRC cell invasion and migration. CONCLUSION These findings imply a crucial involvement of SERPINH1 in the advancement and escalation of CRC, potentially positioning it as a novel candidate for prognostic assessment and therapeutic intervention in CRC management.

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Haj, Amelia K., Sean J. Jurgens, Xin Wang, Justine Ryu, Seung Hoan Choi, Steven P. Grover, Simone Sanna-Cherchi, Alec A. Schmaier, Patrick Ellinor, and Pavan K. Bendapudi. "Rare Germline Loss-of-Function Variants in HSP47 ( SERPINH1) Are Associated with an Intermediate Osteogenesis Imperfecta Phenotype Characterized By Atopic Inflammation and Increased Risk of Thrombosis." Blood 142, Supplement 1 (November 28, 2023): 3934. http://dx.doi.org/10.1182/blood-2023-189896.

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Background: There has been considerable interest in the collagen-specific chaperone HSP47 ( SERPINH1) as a potential drug target for the treatment of cirrhosis, fibrotic disease, and more recently, thrombosis (Thienel et al., Science 380, 178-187, 2023). While homozygous or compound heterozygous loss of function in SERPINH1 is known to cause a rare form of osteogenesis imperfecta (OI) in humans, little is known about the clinical effects of moderately decreased HSP47 activity. In order to assess the potential safety and efficacy of an antithrombotic strategy based on HSP47 blockade, we evaluated the clinical impacts of heterozygous loss-of-function variants in SERPINH1 in a dataset of over 400,000 individuals. Aims: Determine the clinical effects of SERPINH1 loss of function in a large-scale whole exome sequencing dataset. Methods: The UK Biobank (UKBB) contains paired whole exome sequencing and clinical data on 415,921 subjects in addition to plasma proteomics data for a subset of participants (N= 48,892). We identified all rare (MAF<0.1%)variants in SERPINH1 that were predicted in silico to alter protein activity (functional impact score ≥0.7). Using Firth's logistic regression, we controlled for age, sex, ancestry, and other risk factors and assessed the association between the presence of qualifying SERPINH1 variants and four thrombotic disorders: venous thromboembolism (VTE), non-cardioembolic ischemic stroke (NCEIS), myocardial infarction (MI), and peripheral arterial disease (PAD). Replication was performed in a composite dataset from the NIH All of Us program and the Mass General Brigham (MGB) Biobank (N=150,017). We also evaluated differences in the plasma levels of 1,472 proteins (Olink Explore 1536 proteomics panel) between carriers and non-carriers of qualifying SERPINH1 variants. Results: Rare qualifying variants in SERPINH1 were identified in 382 UKBB participants (100% heterozygous). On average, SERPINH1 variant carriers were of significantly shorter stature (P=3.97 x 10-5) and lower weight (P=0.006) than individuals without such variants, and this effect was more pronounced in subjects with higher functional impact scores ( Figure 1). By contrast, bone mineral density did not differ significantly as measured by calcaneal quantitative ultrasound and femur shaft dual x-ray absorptiometry. The presence of SERPINH1 variants was associated with significantly increased risk of VTE (OR=1.87, 95% CI: 1.21-2.76, P=0.006), MI (OR=1.98, 95% CI: 1.27-2.96, P=0.003), PAD (OR=2.37, 95% CI: 1.29-3.98, P=0.007), and NCEIS (OR=2.67, 95% CI: 1.24-4.98, P=0.015). Restricting the analysis to high-confidence loss-of-function variants (i.e., nonsense, frameshift, and essential splice site mutations) markedly boosted effect size estimates for MI, PAD, and NCEIS. The VTE and MI disease associations replicated in the composite dataset (VTE OR=3.29, 95% CI: 1.46-7.39, P=0.004; MI OR=2.31, 95% CI: 1.05-5.08, P=0.038). Additionally, the association with NCEIS demonstrated a strong trend towards significance in the replication dataset (OR=2.08, 95% CI: 0.90-4.83, P=0.088). Plasma proteome analysis showed a significant increase in several proteins related to asthma, atopic inflammation, and/or eosinophil activation among individuals with qualifying SERPINH1 variants, including RNASE3, DPP10, TSPAN1, CCL20, and IL10RA ( Figure 2). In order to further investigate these differences in circulating protein profile, we assessed the risk of obstructive asthma in a meta-analysis of the UKBB, All of Us, and MGB datasets (total N=565,455) and found that SERPINH1 variant carriers were significantly more likely to have disease (OR=1.32, 95% CI: 1.03-1.69, P=0.026). Conclusions: Loss of function in SERPINH1 is associated with a significantly increased risk of both venous and arterial thrombosis, raising concerns that long-term therapeutic inhibition of HSP47 may not be a safe or effective antithrombotic strategy. Our data indicate that SERPINH1 variant carriers experience higher levels of eosinophil-driven inflammation, which has consistently been linked to cardiovascular disease. Further, heterozygous SERPINH1 variant carriers appear to have an intermediate OI phenotype characterized by shorter stature but without significant differences in bone mineral density compared to non-carriers.

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Mueller, S. K., A. L. Nocera, S. T. Dillon, T. A. Libermann, O. Wendler, and B. S. Bleier. "Tissue and Exosomal Serine Protease Inhibitors Are Significantly Overexpressed in Chronic Rhinosinusitis With Nasal Polyps." American Journal of Rhinology & Allergy 33, no. 4 (February 27, 2019): 359–68. http://dx.doi.org/10.1177/1945892419831108.

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Background The fibrinolysis pathway has been previously implicated in the etiopathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). Objective The purpose of this study was (1) to explore protein derangements of selected protease inhibitors of the serpin superfamily in CRSwNP and (2) to correlate the protease inhibitor derangements of the fibrinolysis pathway in tissue with exosomal samples to evaluate the potential of an exosomal noninvasive “liquid biopsy” for CRSwNP. Methods Institutional review board approved study in which matched tissue and mucus exosomal proteins (SerpinB2, SerpinF2, SerpinG1, and SerpinE1) were compared between control and CRSwNP patients using Western Blot analysis (n = 6/group) and immunohistochemistry (IHC). Transcriptome analysis (n = 10/group) on the same proteins was performed using whole transcriptome sequencing. Semiquantitative analysis of the Western Blots was performed using the Whitney–Mann U test. Results The transcriptomic data set showed multiple differentially expressed genes including SerpinB2 (fold changes [FC] 7.38), SerpinE1 (FC 1.42), SerpinF2 (FC 2.03), and SerpinG1 (FC 0.72). Western Blot and IHC analysis showed an overexpression of the Serpin protease inhibitors in tissue (SerpinB2, P < .01; SerpinE1, P < .01; SerpinF2, P < .01; and SerpinG1, P < .01) indicating a downregulation of the fibrinolysis cascade. The mucus exosomal serpin proteins exhibited similar findings. Conclusion Our analysis supported that protease inhibitors of the fibrinolysis pathway, especially SerpinB2, SerpinF2, and SerpinG1, are highly deranged in patients with CRSwNP. These findings suggest a downregulation of the fibrinolysis pathway via proteolytic cascade imbalance leading to excessive polyp fibrin deposition. Our data further supported our hypothesis that exosomal proteomic analyses may be used as noninvasive “liquid biopsy” for CRSwNP and a novel method to study chronic sinonasal inflammation.

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Zhang, Yin, Chun-Yuan Li, Wei Ge, and Yi Xiao. "Exploration of the Key Proteins in the Normal-Adenoma-Carcinoma Sequence of Colorectal Cancer Evolution Using In-Depth Quantitative Proteomics." Journal of Oncology 2021 (June 11, 2021): 1–19. http://dx.doi.org/10.1155/2021/5570058.

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Purpose. In most cases, the carcinogenesis of colorectal cancer (CRC) follows the normal-adenoma-carcinoma (N-A-C) sequence. In this study, we aimed to identify the key proteins in the N-A-C sequence. Methods. Differentially expressed proteins (DEPs) in normal, adenoma, and carcinoma tissues were identified using the Tandem Mass Tag- (TMT-) based quantitative proteomics approach. The landscape of proteomic variation in the N-A-C sequence was explored using gene set enrichment analysis (GSEA) and Proteomaps. Key proteins in the N-A-C sequence were identified, verified, and validated based on our proteomic data, external proteomic data, and external transcriptomic data in the ProteomeXchange, CPTAC, GEO, and TCGA databases. The prognostic value of the key proteins in our database was evaluated by univariate and multivariate Cox regression analysis. The effects of the key proteins on adenoma organoids and colorectal cancer cells were explored in functional studies. Results. Based on our proteomic profiles, we identified 1,294 DEPs between the carcinoma (CG) and normal (NG) groups, 919 DEPs between the adenoma group (AG) and NG, and 1,030 DEPs between the CG and AG. Ribosome- and spliceosome-related pathways were mainly enriched in the N-A process. Extracellular matrix- and epithelial-mesenchymal transition- (EMT-) related pathways were mainly enriched in the A-C process. RRP12 and SERPINH1 were identified, verified, and validated as candidate key proteins in the N-A and A-C processes, respectively. Furthermore, RRP12 and SERPINH1 knockdown impeded the viability and proliferation of adenoma organoids. SERPINH1 was validated as a risk factor for disease-free survival (DFS) based on the TCGA and our database, whereas RRP12 did not show prognostic value. SERPINH1 knockdown was accompanied by EMT-related protein variation, increased apoptosis, and reduced proliferation, invasion, and migration of CRC cells in vitro. Conclusions. RRP12 and SERPINH1 may play an important role in the N-A and A-C processes, respectively. Furthermore, SERPINH1 showed favorable prognostic value for DFS in CRC patients. We speculate that SERPINH1 might promote not only the A-C process but also the development of CRC.

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Bertram, Stefanie, Juliet Padden, Julia Kälsch, Maike Ahrens, Leona Pott, Ali Canbay, Frank Weber, et al. "Novel immunohistochemical markers differentiate intrahepatic cholangiocarcinoma from benign bile duct lesions." Journal of Clinical Pathology 69, no. 7 (January 4, 2016): 619–26. http://dx.doi.org/10.1136/jclinpath-2015-203418.

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AimsThe distinction between intrahepatic cholangiocarcinoma (ICC) and benign bile duct lesions can be challenging. Using our previously identified potential biomarkers for ICC, we examined whether these are useful for the differential diagnosis of ICC, bile duct adenoma and reactive bile duct proliferations in an immunohistochemical approach and identified a diagnostic marker panel including known biomarkers.MethodsSubjects included samples from 77 patients with ICC, 33 patients with bile duct adenoma and 47 patients with ductular reactions in liver cirrhosis. Our previously identified biomarkers (stress-induced phosphoprotein 1 (STIP1), SerpinH1, 14-3-3Sigma) were tested immunohistochemically following comparison with candidates from the literature (cluster of differentiation 56, heat shock protein (HSP)27, HSP70, B-cell-lymphoma2, p53, ki67).ResultsThe expression of SerpinH1 and 14-3-3Sigma was significantly higher in ICC than in bile duct adenomas and ductular reactions (p<0.05), whereas STIP1 expression was significantly higher (p<0.05) in ICC than in ductular reactions, but the difference to the bile duct adenoma group was not significant. A panel of the biomarker SerpinH1, 14-3-3Sigma and ki67 (≥2 marker positive) showed a high diagnostic accuracy (sensitivity 87.8%, specificity 95.9%, accuracy 91.8%) in the differential diagnosis of ICC versus non-malignant bile duct lesions.ConclusionsThis suggests that 14-3-3Sigma and SerpinH1 may be useful in the differential diagnosis of malignant, benign and reactive bile duct lesions in addition to ki67 where a cut-off of >5% might be used for the distinction of malignant and non-malignant lesions.

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Zhang, Yin, Chun-Yuan Li, Meng Pan, Jing-Ying Li, Wei Ge, Lai Xu, and Yi Xiao. "Exploration of the Key Proteins of High-Grade Intraepithelial Neoplasia to Adenocarcinoma Sequence Using In-Depth Quantitative Proteomics Analysis." Journal of Oncology 2021 (November 29, 2021): 1–13. http://dx.doi.org/10.1155/2021/5538756.

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Purpose. In this study, we aimed to provide a comprehensive description of typical features and identify key proteins associated with the high-grade intraepithelial neoplasia- (HIN-) adenocarcinoma (AC) sequence. Methods. We conducted tandem mass tag-based quantitative proteomic profiling of normal mucosa, HIN, and AC tissues. Protein clusters representative of the HIN-AC sequence were identified using heatmaps based on Pearson’s correlation analysis. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome analyses were performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) database, ClueGO plugin in Cytoscape, and the Metascape database. The prognostic value of the key proteins and their effects on the tumor microenvironment and consensus molecular subtype were explored based on The Cancer Genome Atlas. Results. We identified 536 proteins categorized into three clusters. Among the biological processes and pathways of the highly expressed proteins in the HIN-AC sequence, proteins were predominantly enriched in response to gut microbiota, cell proliferation, leukocyte migration, and extracellular matrix (ECM) organization events. SERPINH1 and P3H1 were identified as the key proteins that promote the HIN-AC sequence. In the correlation analysis of infiltrating immune cells, both SERPINH1 and P3H1 expression correlated negatively with tumor purity, while correlating positively with abundance of CD8+ T cells, B cells, macrophage/monocytes, dendritic cells, cancer-associated fibroblasts, endothelial cells, neutrophils, and natural killer cells. Furthermore, both SERPINH1 and P3H1 expression positively correlated with common immune checkpoints and mesenchymal molecular subtype. High P3H1 expression was associated with poor disease-free survival and overall survival. Conclusions. ECM-related biological processes and pathways are typical features of the HIN-AC sequence. SERPINH1 and P3H1 might be the key proteins in this sequence and be related to ECM remodeling and immune suppression status in CRC.

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van Leeuwen, L. Leonie, Mitchel J. R. Ruigrok, Henri G. D. Leuvenink, and Peter Olinga. "Slice of Life: Porcine Kidney Slices for Testing Antifibrotic Drugs in a Transplant Setting." Transplantology 4, no. 2 (April 14, 2023): 59–70. http://dx.doi.org/10.3390/transplantology4020007.

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Circulatory death donor (DCD) kidneys are increasingly used to enlarge the donor pool. These kidneys undergo ischemia-reperfusion injury, frequently leading to renal fibrosis. Transforming growth factor beta 1 (TGF-β1) and matrix metalloproteases have been identified as central mediators of fibrosis and inhibition of these targets could attenuate fibrosis. We studied whether galunisertib, doxycycline, taurine, and febuxostat alleviated fibrosis in precision-cut kidney slices (PCKS). PCKS were prepared from porcine kidneys that were exposed to 30 min of warm ischemia followed by 3 h of oxygenated hypothermic machine perfusion. We subsequently incubated PCKS for 48 h at 37 °C with the described compounds. To further elucidate the antifibrotic effects of galunisertib, we cultured PCKS with TGF-β1. We first screened the effects of the compounds without TGF-β1. Most significant effects were observed for galunisertib which lowered the expression of ACTA2, TGFB1, FN2, and SERPINE1. We then investigated the effects of galunisertib in fibrotic PCKS incubated with TGF-β1. TGF-β1 significantly increased expression of TGFB1, FN1, SERPINE1, and SERPINH1. Galunisertib, however, attenuated the expression of all fibrosis-related genes. Galunisertib appears to be a promising antifibrotic compound requiring further research in a preclinical model and may ultimately be administered during machine perfusion as an antifibrotic treatment in a transplant setting.

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Brzhozovskiy, Alexander G., Alexey S. Kononikhin, Lyudmila Ch Pastushkova, Daria N. Kashirina, Maria I. Indeykina, Igor A. Popov, Marc-Antoine Custaud, Irina M. Larina, and Evgeny N. Nikolaev. "The Effects of Spaceflight Factors on the Human Plasma Proteome, Including Both Real Space Missions and Ground-Based Experiments." International Journal of Molecular Sciences 20, no. 13 (June 29, 2019): 3194. http://dx.doi.org/10.3390/ijms20133194.

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The aim of the study was to compare proteomic data on the effects of spaceflight factors on the human body, including both real space missions and ground-based experiments. LC–MS/MS-based proteomic analysis of blood plasma samples obtained from 13 cosmonauts before and after long-duration (169–199 days) missions on the International Space Station (ISS) and for five healthy men included in 21-day-long head-down bed rest (HDBR) and dry immersion experiments were performed. The semi-quantitative label-free analysis revealed significantly changed proteins: 19 proteins were significantly different on the first (+1) day after landing with respect to background levels; 44 proteins significantly changed during HDBR and 31 changed in the dry immersion experiment. Comparative analysis revealed nine common proteins (A1BG, A2M, SERPINA1, SERPINA3, SERPING1, SERPINC1, HP, CFB, TF), which changed their levels after landing, as well as in both ground-based experiments. Common processes, such as platelet degranulation, hemostasis, post-translational protein phosphorylation and processes of protein metabolism, indicate common pathogenesis in ground experiments and during spaceflight. Dissimilarity in the lists of significantly changed proteins could be explained by the differences in the dynamics of effective development in the ground-based experiments. Data are available via ProteomeXchange using the identifier PXD013305.

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Al-Khatib, Sohaib, Mohammad Nitham Almajali, Ayah Al-Bzour, Joud Al-Ramadneh, Laila Sa'd, and Noor Othman. "Abstract 5594: Exploring genetic determinants: A comprehensive analysis of SERPINB family variants and prognosis in Jordanian glioblastoma multiforme patients." Cancer Research 84, no. 6_Supplement (March 22, 2024): 5594. http://dx.doi.org/10.1158/1538-7445.am2024-5594.

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Abstract Background: Glioblastoma multiforme (GBM) is a major concern with high fatality rate. In Jordan, the incidence of GBM has notably increased, emphasizing the urgency for population-specific research. Serpins are serine proteinase inhibitors, with several Serpins being overexpressed in cancer cells however the exact mechanism by which they affect GBM progression remains unclear. Thus, we aim to analyze the single-nucleotide polymorphism (SNP) of SERPINB11 and its association with GBM survival. Methods: A cohort of 63 GBM patients recruited from King Abdullah University Hospital (KAUH) in Jordan, underwent genomic DNA extraction, polymorphism analysis, and overall survival (OS) assessments. The Serpin B family were validated using The Cancer Genome Atlas (TCGA-GBM) cohort of 160 patients. We constructed a risk-score using the principal component analysis for the following Serpin genes: Serpinb3, Serpinb5, Serpinb6, Serpinb11, and Serpinb12, and patients were grouped into high- vs. low-risk based on median cutoff. Univariable Cox models were used to study the survival outcomes, differential expression analysis between the high- and low-risk groups was carried out to identify the differentially expressed genes (DEGs), gene ontology (GO and tumor microenvironment analyses were carried out. Results: In our primary cohort, we identified a significant association between rs4940595 (SERPINB11) SNP and survival, with the G/T- genotype showing worse prognosis compared to the G/G-T/T genotype in the over dominant model (HR: 2.75, 95% CI: 1.29-5.88, p-value=0.009). In the TCGA validation-cohort, alterations in the SERPINB3gene showed significantly worse OS (Median: 9.53 vs. 14.3, p-value=0.044) compared to the no alteration group. Univariable Cox showed worse PFS outcomes with higher SERPINB5 (HR: 1.67, 95% CI: 1.15-2.43, p-value=0.007) and SERPINB6 expression (HR: 1.44, 95% CI: 1.06-1.96, p-value=0.021). A Serpin B 5-gene risk score was constructed revealing significant association with IDH mutation status and a trend towards worse PFS in the high-risk group. Upregulated DEGs showed GO enrichment in cytokine regulation and production, positive regulation of leukocyte activation and MAPK cascade. While the downregulated DEGs were enriched in forebrain development, and negative regulation of neuron differentiation. The high-risk group showed a significantly higher infiltration of M2 macrophages and activated mast cells. Conclusion: Our findings showed a significant role of the Serpin B family with GBM survival in the Jordanian population. Molecular analyses showed potential mechanisms underlying these associations. Our exploration of SERPINB family and associated SNPs provides valuable insights into the molecular landscape of GBM, paving the way for potential targeted interventions and personalized treatment strategies. Citation Format: Sohaib Al-Khatib, Mohammad Nitham Almajali, Ayah Al-Bzour, Joud Al-Ramadneh, Laila Sa'd, Noor Othman. Exploring genetic determinants: A comprehensive analysis of SERPINB family variants and prognosis in Jordanian glioblastoma multiforme patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5594.

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Zhang, Hailin, Xiaodi Yan, Hongmei Gu, Qiang Xue, and Xiancheng Liu. "High SERPINH1 expression predicts poor prognosis in lung adenocarcinoma." Journal of Thoracic Disease 14, no. 12 (December 2022): 4785–802. http://dx.doi.org/10.21037/jtd-22-1518.

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Zhang, Shuyuan, Weiwei Zhang, Bin Wu, Liang Xia, Liwen Li, Kai Jin, Yangfan Zou, and Caixing Sun. "Hub gene target of glioblastoma: LOX, SERPINH1 and TGFBI." Medicine 101, no. 45 (November 11, 2022): e31418. http://dx.doi.org/10.1097/md.0000000000031418.

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Xia, Kezhou, Xinghan Huang, Yingchun Zhao, Isabelle Yang, and Weichun Guo. "SERPINH1 enhances the malignancy of osteosarcoma via PI3K-Akt signaling pathway." Translational Oncology 39 (January 2024): 101802. http://dx.doi.org/10.1016/j.tranon.2023.101802.

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Cochran, Blake J., David R. Croucher, Sergei Lobov, Darren N. Saunders, and Marie Ranson. "Dependence on Endocytic Receptor Binding via a Minimal Binding Motif Underlies the Differential Prognostic Profiles of SerpinE1 and SerpinB2 in Cancer." Journal of Biological Chemistry 286, no. 27 (May 23, 2011): 24467–75. http://dx.doi.org/10.1074/jbc.m111.225706.

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Tumor overexpression of urokinase-type plasminogen activator (uPA) and its specific inhibitor SerpinE1 (plasminogen activator inhibitor type-1) correlates with poor prognosis and increased metastatic potential. Conversely, tumor expression of uPA and another specific inhibitor, SerpinB2 (plasminogen activator inhibitor type-2), are associated with favorable outcome and relapse-free survival. It is not known how overexpression of these uPA inhibitors results in such disparate outcomes. A possible explanation may be related to the presence of a proposed low density lipoprotein receptor (LDLR)-binding motif in SerpinE1 responsible for mitogenic signaling via ERK that is absent in SerpinB2. We now show that complementation of such a LDLR-binding motif in SerpinB2 by mutagenesis of two key residues enabled high affinity binding to very LDLR (VLDLR). Furthermore, the VLDLR-binding SerpinB2 form behaved in a manner indistinguishable from SerpinE1 in terms of enhanced uPA-SerpinB2 complex endocytosis and subsequent ERK phosphorylation and cell proliferation; that is, the introduction of the LDLR-binding motif to SerpinB2 was necessary and sufficient to allow it to acquire characteristics of SerpinE1 associated with malignancy. In conclusion, this study defines the structural elements underlying the distinct interactions of SerpinE1 versus SerpinB2 with endocytic receptors and how differential VLDLR binding impacts on downstream cellular behavior. This has clear relevance to understanding the paradoxical disease outcomes associated with overexpression of these serpins in cancer.

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Charone, Senda, Erika Calvano Küchler, Aline de Lima Leite, Mileni Silva Fernandes, Vinicius Taioqui Pelá, Tatiana Martini, Bárbara Margarido Brondino, et al. "Analysis of Polymorphisms in Genes Differentially Expressed in the Enamel of Mice with Different Genetic Susceptibilities to Dental Fluorosis." Caries Research 53, no. 2 (August 27, 2018): 228–33. http://dx.doi.org/10.1159/000491554.

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Genes expressed during amelogenesis are candidates to increase the risk of dental fluorosis (DF). Thus, this study aimed to evaluate the association between polymorphisms in enamel development genes and susceptibility to DF in mice. Mice of both sexes, representing strains 129P3/J (n = 20; resistant to DF) and A/J (n = 20; susceptible to DF), were divided into 2 groups. Each strain received a diet with a low concentration of fluoride (F) and drinking water containing 0 or 50 mg/L of F for 6 weeks. Clinical evaluation and analysis of Vickers enamel microhardness of the incisors were performed. Livers were collected for genomic DNA extraction. Seventeen genetic polymorphisms in Amelx, Ambn, Ambn, Col14a1, Col1a1, Col5a2, Enam, Fam20a, Fam83h, Foxo1, Klk4, Mmp20, Serpinf1, Serpinh1, Smad3, Tuft1, and Wdr72 were genotyped by real-time PCR using Taqman chemistry. Overrepresentation of alleles and genotypes in DF was evaluated using the χ2 test with an alpha of 5%. The clinical aspects of the enamel and the surface enamel microhardness confirmed the DF condition. In the polymorphisms rs29569969, rs13482592, and rs13480057 in Ambn, Col14a1, and Mmp20, respectively, genotype and allele distributions were statistically significantly different between A/J and 129P3/J strains (p < 0.05). In conclusion, polymorphisms in Ambn, Col14a1, and Mmp20 are associated with the susceptibility to DF.

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Drögemüller, Cord, Doreen Becker, Adrian Brunner, Bianca Haase, Patrick Kircher, Frank Seeliger, Michael Fehr, Ulrich Baumann, Kerstin Lindblad-Toh, and Tosso Leeb. "A Missense Mutation in the SERPINH1 Gene in Dachshunds with Osteogenesis Imperfecta." PLoS Genetics 5, no. 7 (July 24, 2009): e1000579. http://dx.doi.org/10.1371/journal.pgen.1000579.

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Winkler, Ingrid G., Jean Hendy, Paul Coughlin, Anita Horvath, and Jean-Pierre Lévesque. "Serine protease inhibitors serpina1 and serpina3 are down-regulated in bone marrow during hematopoietic progenitor mobilization." Journal of Experimental Medicine 201, no. 7 (March 28, 2005): 1077–88. http://dx.doi.org/10.1084/jem.20042299.

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Mobilization of hematopoietic progenitor cells into the blood involves a massive release of neutrophil serine proteases in the bone marrow. We hypothesize that the activity of these neutrophil serine proteases is regulated by the expression of naturally occurring inhibitors (serpina1 and serpina3) produced locally within the bone marrow. We found that serpina1 and serpina3 were transcribed in the bone marrow by many different hematopoietic cell populations and that a strong reduction in expression occurred both at the protein and mRNA levels during mobilization induced by granulocyte colony-stimulating factor or chemotherapy. This decreased expression was restricted to the bone marrow as serpina1 expression was maintained in the liver, leading to no change in plasma concentrations during mobilization. The down-regulation of serpina1 and serpina3 during mobilization may contribute to a shift in the balance between serine proteases and their inhibitors, and an accumulation of active neutrophil serine proteases in bone marrow extravascular fluids that cleave and inactivate molecules essential to the retention of hematopoietic progenitor cells within the bone marrow. These data suggest an unexpected role for serpina1 and serpina3 in regulating the bone marrow hematopoietic microenvironment as well as influencing the migratory behavior of hematopoietic precursors.

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Kranc, Wiesława, Maciej Brązert, Katarzyna Ożegowska, Joanna Budna-Tukan, Piotr Celichowski, Maurycy Jankowski, Artur Bryja, et al. "Response to abiotic and organic substances stimulation belongs to ontologic groups significantly up-regulated in porcine immature oocytes." Medical Journal of Cell Biology 6, no. 3 (December 1, 2018): 91–100. http://dx.doi.org/10.2478/acb-2018-0015.

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Abstract The efficiency of the process of obtaining mature oocytes, and then of porcine embryos in vitro depends on many factors and requires meeting many conditions. These include selection of morphologically appropriate oocytes, selection of appropriate medium components, as well as a number of abiotic factors (appropriate microenvironment during in vitro culture). Oocytes were taken from 45 pubertal crossbred Landrace gilts. The BCB test was carried out. BCB + oocytes were divided into two groups: “before IVM” and “after IVM”. “Before IVM” oocytes were subjected to molecular analyzes immediately after collection, while “after IVM” oocytes underwent in vitro maturation and then the second BCB test. Oocytes that remained BCB+ after the second test were used for molecular analyzes using Affymetrix expression microarrays. A group of genes responsible for response to organic substance and response to abiotic stimulus, which underwent significant changes (decrease) was discovered after oocyte in vitro maturation. Genes such as MM, PLDP, SERPINH, MYOF, DHX9, HSPA5, VCP, KIT, SERPINH1, PLD1, and VCP showed the largest decrease after the culture period. The levels of these genes were therefore elevated in oocytes before the in vitro maturation process. In conclusion, a number of organic and abiotic factors have an impact on the process of the oocyte in vitro maturation. The presented results confirm the literature data in which the low efficiency of obtaining mature oocytes in in vitro conditions is mentioned, which further impacts the amount of viable embryos obtained.

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Zapata, Liliana Mejia. "Novel heterozygous mutations in gene SERPINH1 cause autosomal recessive osteogenesis imperfecta type X." Bone Reports 14 (April 2021): 100994. http://dx.doi.org/10.1016/j.bonr.2021.100994.

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Kishimoto, Yo, Masaru Yamashita, Alice Wei, Yutaka Toya, Shuyun Ye, Christina Kendziorski, and Nathan V. Welham. "Reversal of Vocal Fold Mucosal Fibrosis Using siRNA against the Collagen-Specific Chaperone Serpinh1." Molecular Therapy - Nucleic Acids 16 (June 2019): 616–25. http://dx.doi.org/10.1016/j.omtn.2019.04.014.

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Song, Y., D. Zhao, X. Xu, F. Lv, L. Li, Y. Jiang, O. Wang, W. Xia, X. Xing, and M. Li. "Novel compound heterozygous mutations in SERPINH1 cause rare autosomal recessive osteogenesis imperfecta type X." Osteoporosis International 29, no. 6 (March 9, 2018): 1389–96. http://dx.doi.org/10.1007/s00198-018-4448-2.

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Tian, Shan, Pailan Peng, Jiao Li, Huan Deng, Na Zhan, Zhi Zeng та Weiguo Dong. "SERPINH1 regulates EMT and gastric cancer metastasis via the Wnt/β-catenin signaling pathway". Aging 12, № 4 (24 лютого 2020): 3574–93. http://dx.doi.org/10.18632/aging.102831.

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Burgener, Sabrina S., Mathias Baumann, Paola Basilico, Eileen Remold-O’Donnell, Ivo P. Touw, and Charaf Benarafa. "Myeloid conditional deletion and transgenic models reveal a threshold for the neutrophil survival factor Serpinb1." Biological Chemistry 397, no. 9 (September 1, 2016): 897–905. http://dx.doi.org/10.1515/hsz-2016-0132.

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Abstract Serpinb1 is an inhibitor of neutrophil granule serine proteases cathepsin G, proteinase-3 and elastase. One of its core physiological functions is to protect neutrophils from granule protease-mediated cell death. Mice lacking Serpinb1a (Sb1a-/-), its mouse ortholog, have reduced bone marrow neutrophil numbers due to cell death mediated by cathepsin G and the mice show increased susceptibility to lung infections. Here, we show that conditional deletion of Serpinb1a using the Lyz2-cre and Cebpa-cre knock-in mice effectively leads to recombination-mediated deletion in neutrophils but protein-null neutrophils were only obtained using the latter recombinase-expressing strain. Absence of Serpinb1a protein in neutrophils caused neutropenia and increased granule permeabilization-induced cell death. We then generated transgenic mice expressing human Serpinb1 in neutrophils under the human MRP8 (S100A8) promoter. Serpinb1a expression levels in founder lines correlated positively with increased neutrophil survival when crossed with Sb1a-/- mice, which had their defective neutrophil phenotype rescued in the higher expressing transgenic line. Using new conditional and transgenic mouse models, our study demonstrates the presence of a relatively low Serpinb1a protein threshold in neutrophils that is required for sustained survival. These models will also be helpful in delineating recently described functions of Serpinb1 in metabolism and cancer.

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Alhalabi, O., M. Göttmann, M. Gold, M. Fletcher, T. Hielscher, M. Iskar, T. Kessler, et al. "P04.04 Optimizing dasatinib for glioblastoma treatment." Neuro-Oncology 23, Supplement_2 (September 1, 2021): ii19. http://dx.doi.org/10.1093/neuonc/noab180.061.

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Abstract BACKGROUND Glioblastoma is the most common primary malignancy of the central nervous system with a dismal prognosis, even with surgical and chemoradiotherapy. Expression profiling studies classify IDH-wildtype Glioblastoma into three subtypes: Proneural (PN), mesenchymal (MES) and classical (CL). A promising target to inhibit in Glioblastoma is the non-receptor tyrosine kinase and proto-oncogene SRC. After robust pre-clinical results, SRC inhibitors like dasatinib did not improve survival of Glioblastoma patients after recurrence in clinical trials. MATERIAL AND METHODS Consolidating efforts to personalize cancer therapy, we use in silico analyses backed by in vitro and in vivo experiments on Glioblastoma stem-like cells (GSCs) derived from primary patient tumors to present a novel stratification strategy for dasatinib therapy in glioblastoma. To further tackle dasatinib resistance in GSCs, a pooled shRNA library against 5000 genes was combined with dasatinib to identify genes whose knockdown sensitizes GSCs to dasatinib. This was integrated with proteomics and phosphoproteomics data of dasatinib inhibited GSCs. RESULTS We found MES tumors with high expression of SERPINH1 to be sensitive to dasatinib inhibition, compared to the CL and PN subtypes. Interestingly, SRC phosphorylation status did not predict the efficacy of dasatinib inhibition. Computational analyses integrating data from the loss-of-function dropout viability screen and proteomics/phosphoproteomics using a novel modification of the SamNet algorithm identified Wee1, a tyrosine kinase involved in cell-cycle signaling, as a potential combination inhibition target with dasatinib. Further validation experiments showed a robust synergistic effect through combination of dasatinib and the wee1 inhibitor, MK-1775 in PN GSCs. CONCLUSION This study highlights strategies to optimize dasatinib treatment in different glioblastoma subtypes. While the stratification of patients harboring mesenchymal glioblastoma with SERPINH1 overexpression could provide an option in this particular subtype, combining dasatinib or other SRC inhibitors with Wee1 inhibitors could present an additional possibility for treating resistant proneural tumors

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Huang, H., T. Chen, L. Zhen, L. Yiming, P. Shengmeng, C. Yongming, L. Lingfeng, Z. Jie, and G. Zhenghui. "Mechanism of SERPINH1 in promoting bone metastasis of prostate cancer by inhibiting P62 ubiquitination degradation." European Urology 83 (February 2023): S1661. http://dx.doi.org/10.1016/s0302-2838(23)01186-7.

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Sivaprasad, Umasundari, Kayla Kinker, Aaron Gibson, Stacey Bass, Nicolas Hershey, Jocelyn Biagini Myers, Melinda Butsch Kovacic, Lisa Martin, and Gurjit Khurana Hershey. "Role of SERPINB3, SERPINB4, and their mouse homolog Serpinb3a in allergen-induced cutaneous inflammation. (P3347)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 210.5. http://dx.doi.org/10.4049/jimmunol.190.supp.210.5.

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Abstract The serine protease inhibitors SERPINB3 and SERPINB4 have been implicated in allergic disorders. We have recently demonstrated a role for the serine protease inhibitor Serpinb3a (the mouse homolog of SERPINB3 and SERPINB4) in a mouse model of asthma. Elevated levels of SERPINB3 and SERPINB4 are detected in the serum of patients with atopic dermatitis (AD) and they have been proposed as possible biomarkers for AD. Serine proteases are critical for epidermal barrier homeostasis and aberrant expression and/or activity of serine proteases have been associated with AD in human studies. We also observe a significant induction in the expression of Serpinb3a in a mouse model of cutaneous inflammation that has many similarities to AD. However the role of Serpinb3a in the skin is unknown. Using our mouse model of skin inflammation, we observed attenuation in trans-epidermal water loss, skin inflammation scores, decreased levels of total IgE, and pro-inflammatory markers like S100A8 in mice lacking Serpinb3a following exposure to Aspergillus fumigatus extract. In humans, we have identified a single nucleotide polymorphism (SNP) in the locus that encodes SERPINB3 and SERPINB4 that is associated with trans-epidermal water loss (p-val=0.031). In conclusion, we demonstrate that SERPINB3 and SERPINB4 contribute to cutaneous inflammation and work is ongoing to elucidate the role of this protein in regulating the skin barrier.

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Gajewski, T., Y. Zha, B. Thurner, and G. Schuler. "Association of gene expression profile in metastatic melanoma and survival to a dendritic cell-based vaccine." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 9002. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.9002.

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9002 Background: Emerging data suggests that features of the melanoma tumor microenvironment may determine the clinical outcome to immunotherapies. We recently have observed a gene expression signature that correlated with a favorable clinical outcome in response to an IL-12-based melanoma vaccine. Increased expression of chemokine genes and T cell transcripts, and decreased expression of genes associated with aggressive tumor biology, were observed in the favorable group. To determine whether these patterns were reproducible, gene expression profiling was performed from an independent vaccine clinical trial. Methods: Patients with advanced melanoma were treated with autologous, mature monocyte-derived dendritic cells loaded with a combination of melanoma antigen peptides. Pretreatment biopsies were cryopreserved for RNA extraction and gene expression profiling. Patients were categorized into “long survival” (> 24 months) or “short survival” outcomes. Supervised hierarchical clustering was performed to identify genes differentially expressed in the two outcome groups. Results: RNA that passed quality control was obtained from 17 stage IV patients, 5 with a short survival and 12 with a long survival. 408 genes were differentially at least 2- fold. Consistent with previous observations, tumors from favorable outcome patients expressed higher levels of several T cell-specific genes, including Thy1 and CD28; chemokines, including CCL19, CXCL12, and CXCL14; and other immune genes, including LTβ, IL-1R, IFNαR2, IL27R, CD69, and FcRs. Conversely, tumors from unfavorable outcome patients expressed higher levels of pro- angiogeneic genes, including Flt1; anti-apoptotic genes, including SerpinH1 and Serpine1; and multiple collagens. Conclusions: Our results confirm that a subset of transcripts expressed in melanoma metastases may be useful as a predictive biomarker for response to melanoma vaccines. The categories of genes identified point toward new opportunities for overcoming resistance mechanisms. Future studies should integrate gene expression profiling of pre-treatment biopsies as a stratification or enrichment factor in immunotherapy trials. No significant financial relationships to disclose.

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Kamikawaji, Kazuto, Naohiko Seki, Masaki Watanabe, Hiroko Mataki, Tomohiro Kumamoto, Koichiro Takagi, Keiko Mizuno, and Hiromasa Inoue. "Regulation of LOXL2 and SERPINH1 by antitumor microRNA-29a in lung cancer with idiopathic pulmonary fibrosis." Journal of Human Genetics 61, no. 12 (August 4, 2016): 985–93. http://dx.doi.org/10.1038/jhg.2016.99.

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Razali, Nurhanani, Azlina Abdul Aziz, Chor Yin Lim, and Sarni Mat Junit. "Investigation into the effects of antioxidant-rich extract ofTamarindus indicaleaf on antioxidant enzyme activities, oxidative stress and gene expression profiles in HepG2 cells." PeerJ 3 (October 1, 2015): e1292. http://dx.doi.org/10.7717/peerj.1292.

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The leaf extract ofTamarindus indicaL. (T. indica) had been reported to possess high phenolic content and showed high antioxidant activities. In this study, the effects of the antioxidant-rich leaf extract of theT. indicaon lipid peroxidation, antioxidant enzyme activities, H2O2-induced ROS production and gene expression patterns were investigated in liver HepG2 cells. Lipid peroxidation and ROS production were inhibited and the activity of antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase was enhanced when the cells were treated with the antioxidant-rich leaf extract. cDNA microarray analysis revealed that 207 genes were significantly regulated by at least 1.5-fold (p< 0.05) in cells treated with the antioxidant-rich leaf extract. The expression ofKNG1, SERPINC1, SERPIND1, SERPINE1, FGG, FGA, MVK, DHCR24, CYP24A1,ALDH6A1, EPHX1andLEAP2were amongst the highly regulated. When the significantly regulated genes were analyzed using Ingenuity Pathway Analysis software, “Lipid Metabolism, Small Molecule Biochemistry, Hematological Disease” was the top biological network affected by the leaf extract, with a score of 36. The top predicted canonical pathway affected by the leaf extract was the coagulation system (P< 2.80 × 10−6) followed by the superpathway of cholesterol biosynthesis (P< 2.17 × 10−4), intrinsic prothrombin pathway (P< 2.92 × 10−4), Immune Protection/Antimicrobial Response (P< 2.28 × 10−3) and xenobiotic metabolism signaling (P< 2.41 × 10−3). The antioxidant-rich leaf extract ofT. indicaalso altered the expression of proteins that are involved in the Coagulation System and the Intrinsic Prothrombin Activation Pathway (KNG1, SERPINE1, FGG), Superpathway of Cholesterol Biosynthesis (MVK), Immune protection/antimicrobial response (IFNGR1, LEAP2, ANXA3 and MX1) and Xenobiotic Metabolism Signaling (ALDH6A1, ADH6). In conclusion, the antioxidant-rich leaf extract ofT. indicainhibited lipid peroxidation and ROS production, enhanced antioxidant enzyme activities and significantly regulated the expression of genes and proteins involved with consequential impact on the coagulation system, cholesterol biosynthesis, xenobiotic metabolism signaling and antimicrobial response.

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Kantaputra, Piranit, Teerada Daroontum, Mati Chuamanochan, Suteeraporn Chaowattanapanit, Salin Kiratikanon, Charoen Choonhakarn, Worrachet Intachai, et al. "SERPINB3, Adult-Onset Immunodeficiency, and Generalized Pustular Psoriasis." Genes 14, no. 2 (January 19, 2023): 266. http://dx.doi.org/10.3390/genes14020266.

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Background: Generalized pustular psoriasis (GPP; MIM 614204) is a rare and severe pustular autoinflammatory skin disease in which acute generalized erythema and scaling develop with numerous sterile pustules. GPP shares skin manifestations, especially pustular skin reaction, with adult-onset immunodeficiency (AOID) with anti-interferon-γ autoantibodies, an autoimmune disease. Methods: Clinical examinations and whole-exome sequencing (WES) were performed on 32 patients with pustular psoriasis phenotypes and 21 patients with AOID with pustular skin reaction. Immunohistochemical and histopathological studies were performed. Results: WES identified three Thai patients presenting with similar pustular phenotypes—two with a diagnosis of AOID and the other with GPP. A heterozygous missense variant chr18:g.61325778C>A NM_006919.2: c.438G>T; NP_008850.1: p.Lys146Asn; rs193238900 in SERPINB3 was identified in two patients: one with GPP and the other with AOID. The other patient who had AOID carried a heterozygous missense variant chr18:g.61323147T>C NM_006919.2: c.917A>G; NP_008850.1: p.Asp306Gly in SERPINB3. Immunohistochemical studies showed overexpression of SERPINA1 and SERPINB3, a hallmark of psoriatic skin lesions. Conclusions: Genetic variants in SERPINB3 are associated with GPP and AOID with pustular skin reaction. The skin of patients with GPP and AOID carrying SERPINB3 mutations showed overexpression of SERPINB3 and SERPINA1. Clinically and genetically, GPP and AOID appear to share pathogenetic mechanisms.

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Fazlic, M., R. Fairclough, S. Fraser, R. Young, G. Jenkin, M. Knight, and M. McDonagh. "434. Identification of differentially expressed proteins in ovine chorion rupture sites at preterm and term using proteomics." Reproduction, Fertility and Development 20, no. 9 (2008): 114. http://dx.doi.org/10.1071/srb08abs434.

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Introduction: A significant number of babies are delivered preterm and many of these deliveries are due to spontaneous rupture of fetal membranes. However, the mechanisms underlying fetal membrane rupture are not well defined. The sheep has proved to be a valuable model for elucidating the physiology of birth, with many of the findings clearly relevant to human parturition. In the current study we have used the sheep model to investigate changes in protein expression in the chorion in relation to the onset of spontaneous full term labour. Methods: Proteomic analysis was used to compare the protein profiles at the chorion rupture site between mid/late gestation (136 days, n = 6) and term delivery (145days, n = 6). Proteins were solubilised and separated into soluble and insoluble fractions which were separated by 2D-electrophoresis. Relative protein expression was quantified using the PROGENESIS software and protein spots were picked and identified using Matrix Assisted Laser Desorption Ionisation-Time of Flight (MALDI-TOF) mass spectrometry. Data-mining used gene ontology (GO terms) for each protein and these were clustered into networks using DAVID bioinformatics resource (http://david.abcc.ncifcrf.gov/home.jsp). Results: A total of 150 protein spots were identified of which 60 proteins were found to differ by more than 2-fold between preterm and term samples. This group was significantly enriched for proteins from the several functional GO categories including; Oxidoreductase activity (7 proteins); negative regulation of apoptosis (4); structural molecule activity (7); protease inhibitor activity (7); Carbohydrate metabolism (10); Glucose metabolism (5); Glycolysis (5); response to stress (8) and heat shock (3). Of the differentially regulated proteins, 10 were found to be significantly upregulated at term (ANOVA P < 0.05) including isocitrate dehydrogenase, glutamate dehydrogenase 1, malate dehydrogenase 2. A further 10 proteins, including serpin peptidase inhibitor SERPINA12, serpin peptidase inhibitor SERPINH1 precursor and heat shock protein 90 kDa β were found to be downregulated.

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Kawagoe, Kosuke, Masumi Wada, Tetsuya Idichi, Reona Okada, Yasutaka Yamada, Shogo Moriya, Keishi Okubo, et al. "Regulation of aberrantly expressed SERPINH1 by antitumor miR-148a-5p inhibits cancer cell aggressiveness in gastric cancer." Journal of Human Genetics 65, no. 8 (March 31, 2020): 647–56. http://dx.doi.org/10.1038/s10038-020-0746-6.

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Marshall, Charlotte, Jaime Lopez, Laura Crookes, Rebecca C. Pollitt, and Meena Balasubramanian. "A novel homozygous variant in SERPINH1 associated with a severe, lethal presentation of osteogenesis imperfecta with hydranencephaly." Gene 595, no. 1 (December 2016): 49–52. http://dx.doi.org/10.1016/j.gene.2016.09.035.

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Pomerleau, V., V. Reyes-Nicolas, C. Jurkovic, F. Boisvert, and N. Perreault. "A7 FOXL1+ TELOCYTES IN MOUSE COLON ORCHESTRATE ECM BIODYNAMICS AND WOUND REPAIR RESOLUTION." Journal of the Canadian Association of Gastroenterology 5, Supplement_1 (February 21, 2022): 8–9. http://dx.doi.org/10.1093/jcag/gwab049.006.

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Abstract Background The extracellular matrix (ECM) is a complex assembly of proteins that provide mechanical and biochemical stimuli to the epithelial and mesenchymal cells of the GI mucosa. Deficiencies in ECM assembly, protein production or excessive accumulation can lead to multiples pathologies including fibrosis and cancer. FoxL1+-Telocytes (TCFoxL1+) are subepithelial cells that form a network underneath the epithelium, contributing to the microenvironment that supports epithelial and immune cell homeostasis. We have previously shown that BMPR1A signaling deletion in TCFoxL1+ influences the microenvironment via stromagenesis, immune infiltration and colonic dysplasia in mouse model of GI diseases. However, the precise molecular and mechanical events that contributes to the onset of this state have yet to be elucidated. Aims Characterize the modulations in ECM biodynamics induced by BmpR1a-deficient TC FoxL1+ ( BmpR1a△FoxL1+) in mouse colon submucosa. Methods Matrisomics was performed to determine the inventory of ECM proteins expressed solely in the GI stromal compartment following tissue deconstruction of control and BmpR1a△FoxL1+ mice colons. Histological and biochemical methods were used to further characterize the collagen network and matrisome-associated modulations. Fluorescence In Situ Hybridization (FISH) was performed to study the bacterial presence in the mucosa. Results The set of identified proteins shows an enrichment for proteins involved in collagen network regulation, wound repair homeostasis and immune regulation such as Col1a2, Col3a1, Col6a4 and Coll14a1, as well as SerpinH1, MFAP4, ANXA1 and S100A9. Collagen network is affected with increased deposition and reorganization of fiber alignment. Unfolded collagen content was also increased in dysplastic areas of BmpR1a△FoxL1+ mouse colon with a concomitant increase in the collagen-chaperone SerpinH1. Validations of other targets indicate that BmpR1a△FoxL1+ mice deals with some type of tissue micro-injury and inflammation that is unresolved, creating a unfavorable microenvironment for tissue homeostasis. Conclusions Taken together, these results suggest that Bmp-signaling deficient TCFoxL1+ significantly contribute to the collagen network biodynamics through increased collagen deposition, fiber alignment reorganization and regulation of the collagen triple-helix assembly. Other matrisome modulations suggest a state of unresolved wound healing due to tissue injury, that could be the etiology of GI pathology and lead to more severe conditions upon various environmental triggers. Funding Agencies CIHR

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Crawford, Andrew A., Sean Bankier, Elisabeth Altmaier, Catriona L. K. Barnes, David W. Clark, Raili Ermel, Nele Friedrich, et al. "Variation in the SERPINA6/SERPINA1 locus alters morning plasma cortisol, hepatic corticosteroid binding globulin expression, gene expression in peripheral tissues, and risk of cardiovascular disease." Journal of Human Genetics 66, no. 6 (January 20, 2021): 625–36. http://dx.doi.org/10.1038/s10038-020-00895-6.

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AbstractThe stress hormone cortisol modulates fuel metabolism, cardiovascular homoeostasis, mood, inflammation and cognition. The CORtisol NETwork (CORNET) consortium previously identified a single locus associated with morning plasma cortisol. Identifying additional genetic variants that explain more of the variance in cortisol could provide new insights into cortisol biology and provide statistical power to test the causative role of cortisol in common diseases. The CORNET consortium extended its genome-wide association meta-analysis for morning plasma cortisol from 12,597 to 25,314 subjects and from ~2.2 M to ~7 M SNPs, in 17 population-based cohorts of European ancestries. We confirmed the genetic association with SERPINA6/SERPINA1. This locus contains genes encoding corticosteroid binding globulin (CBG) and α1-antitrypsin. Expression quantitative trait loci (eQTL) analyses undertaken in the STARNET cohort of 600 individuals showed that specific genetic variants within the SERPINA6/SERPINA1 locus influence expression of SERPINA6 rather than SERPINA1 in the liver. Moreover, trans-eQTL analysis demonstrated effects on adipose tissue gene expression, suggesting that variations in CBG levels have an effect on delivery of cortisol to peripheral tissues. Two-sample Mendelian randomisation analyses provided evidence that each genetically-determined standard deviation (SD) increase in morning plasma cortisol was associated with increased odds of chronic ischaemic heart disease (0.32, 95% CI 0.06–0.59) and myocardial infarction (0.21, 95% CI 0.00–0.43) in UK Biobank and similarly in CARDIoGRAMplusC4D. These findings reveal a causative pathway for CBG in determining cortisol action in peripheral tissues and thereby contributing to the aetiology of cardiovascular disease.

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Widmer, C., J. M. Gebauer, E. Brunstein, S. Rosenbaum, F. Zaucke, C. Drogemuller, T. Leeb, and U. Baumann. "Molecular basis for the action of the collagen-specific chaperone Hsp47/SERPINH1 and its structure-specific client recognition." Proceedings of the National Academy of Sciences 109, no. 33 (July 30, 2012): 13243–47. http://dx.doi.org/10.1073/pnas.1208072109.

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Haj, A., S. Jurgens, X. Wang, J. Ryu, S. Choi, S. Grover, P. Ellinor, and P. Bendapudi. "LB 01.4 Rare Germline Loss of Function Variants in SERPINH1 (HSP47) are Associated with Increased Risk of Thrombosis." Research and Practice in Thrombosis and Haemostasis 7 (October 2023): 100291. http://dx.doi.org/10.1016/j.rpth.2023.100291.

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Zvereff, Val, Azza Abd El Moneim Attia, Amal Al Tenaiji, Sana Islam, Anushree Dileep, and Shalini Behl. "P699: Identification of a novel pathogenic variant in SERPINH1 associated with a presentation of osteogenesis imperfecta: Case study." Genetics in Medicine Open 2 (2024): 101603. http://dx.doi.org/10.1016/j.gimo.2024.101603.

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Marques, Patrícia Isabel, Zélia Ferreira, Manuella Martins, Joana Figueiredo, Diana Isabel Silva, Patrícia Castro, Ramiro Morales-Hojas, Joana Simões-Correia, and Susana Seixas. "SERPINA2 Is a Novel Gene with a Divergent Function from SERPINA1." PLoS ONE 8, no. 6 (June 24, 2013): e66889. http://dx.doi.org/10.1371/journal.pone.0066889.

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Kloth, JN, A. Gorter, GJ Fleuren, J. Oosting, S. Uljee, N. ter Haar, EJ Dreef, GG Kenter, and ES Jordanova. "Elevated expression of SerpinA1 and SerpinA3 in HLA-positive cervical carcinoma." Journal of Pathology 215, no. 3 (July 2008): 222–30. http://dx.doi.org/10.1002/path.2347.

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Li, Mengdi, Shuheng Huang, Yong Zhang, Zhi Song, Haijun Fu, Zhengmei Lin та Xin Huang. "Regulation of the unfolded protein response transducer IRE1α by SERPINH1 aggravates periodontitis with diabetes mellitus via prolonged ER stress". Cellular Signalling 91 (березень 2022): 110241. http://dx.doi.org/10.1016/j.cellsig.2022.110241.

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Wu, Gang, Xueming Ju, Youyu Wang, Zhixi Li, and Xianfeng Gan. "Up-regulation of SNHG6 activates SERPINH1 expression by competitive binding to miR-139-5p to promote hepatocellular carcinoma progression." Cell Cycle 18, no. 16 (July 1, 2019): 1849–67. http://dx.doi.org/10.1080/15384101.2019.1629772.

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Wang, Yanni, Zhe Liu, Zhen Li, Haina Shi, Yujun Kang, Jianfu Wang, Jinqiang Huang, and Li Jiang. "Effects of heat stress on respiratory burst, oxidative damage and SERPINH1 (HSP47) mRNA expression in rainbow trout Oncorhynchus mykiss." Fish Physiology and Biochemistry 42, no. 2 (November 27, 2015): 701–10. http://dx.doi.org/10.1007/s10695-015-0170-6.

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Bostanci, Mehmet Suhha, Merih Bayram, Suleyman Murat Bakacak, Ozge Kizilkale Yildirim, Rukset Attar, Gazi Yildirim, Emin Umit Bagriacik, and Baran Celtemen. "The role of TWIST, SERPINB5, and SERPIN1 genes in uterine leiomyomas." Journal of the Turkish German Gynecological Association 15, no. 2 (June 16, 2014): 92–95. http://dx.doi.org/10.5152/jtgga.2014.13005.

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Christiansen, Helena E., Ulrike Schwarze, Shawna M. Pyott, Abdulrahman AlSwaid, Mohammed Al Balwi, Shatha Alrasheed, Melanie G. Pepin, Mary Ann Weis, David R. Eyre, and Peter H. Byers. "Homozygosity for a Missense Mutation in SERPINH1, which Encodes the Collagen Chaperone Protein HSP47, Results in Severe Recessive Osteogenesis Imperfecta." American Journal of Human Genetics 86, no. 3 (March 2010): 389–98. http://dx.doi.org/10.1016/j.ajhg.2010.01.034.

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46

Wahlmüller, Felix Christof, Barbora Sokolikova, Daniela Rieger, and Margarethe Geiger. "New lipid interaction partners stimulate the inhibition of activated protein C by cell-penetrating protein C inhibitor." Thrombosis and Haemostasis 111, no. 01 (2014): 41–52. http://dx.doi.org/10.1160/th13-06-0478.

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SummaryProtein C inhibitor (PCI, SerpinA5) is a heparin-binding serpin which can penetrate through cellular membranes. Selected negatively charged phospholipids like unsaturated phosphatidylserine and oxidised phosphatidylethanolamine bind to PCI and stimulate its inhibitory activity towards different proteases. The interaction of phospholipids with PCI might also alter the lipid distribution pattern of blood cells and influence the remodelling of cellular membranes. Here we showed that PCI is an additional binding partner of phosphatidic acid (PA), cardiolipin (CL), and phosphoinositides (PIPs). Protein lipid overlay assays exhibited a unique binding pattern of PCI towards different lipid species. In addition PA, CL, and unsaturated, monophosphorylated PIPs stimulated the inhibitory property of PCI towards activated protein C in a heparin like manner. As shown for kallistatin (SerpinA4) and vaspin (SerpinA12), the incubation of cells with PCI led to the activation of protein kinase B (AKT), which could be achieved through direct interaction of PCI with PIPs. This model is supported by the fact that PCI stimulated the PIP-dependent 5-phosphatase SHIP2 in vitro, which would result in AKT activation. Hence the interaction of PCI with different lipids might not only stimulate the inhibition of potential target protease by PCI, but could also alter intracellular lipid signalling.

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Wang, H., S. Parry, G. Macones, M. D. Sammel, H. Kuivaniemi, G. Tromp, G. Argyropoulos, et al. "A functional SNP in the promoter of the SERPINH1 gene increases risk of preterm premature rupture of membranes in African Americans." Proceedings of the National Academy of Sciences 103, no. 36 (August 28, 2006): 13463–67. http://dx.doi.org/10.1073/pnas.0603676103.

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Lee, Eun-Ju, Daniel Dykas, Allen Bale, Caroline Cromwell, Terri L. Parker, Stephanie Halene, Adrienne Burns, Xiaopan Yao, and Alfred I. Lee. "Whole Exome Sequencing in Evaluation of Thrombophilia: A Novel 33-Gene Panel." Blood 126, no. 23 (December 3, 2015): 3529. http://dx.doi.org/10.1182/blood.v126.23.3529.3529.

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Abstract Introduction: Venous thromboembolism (VTE) occurs with an incidence of 1-2 per 1000 individuals per year. Approximately 10-20% of patients with VTE have a heritable thrombophilia involving one of five known genes: Factor V, prothrombin (PT), antithrombin (AT), protein C (PC), and protein S (PS). Significant variability of laboratory functional assays as well as fluctuating plasma levels of AT, PC and PS lead not only to delay in initial thrombophilia screening but also to multiple rounds of costly testing. Whole exome sequencing (WES) is a potentially useful diagnostic tool for inherited thrombophilias as it avoids dependence on laboratory and situational variation in protein levels. We compiled a panel of 33 genes involved in thrombosis with a goal of investigating the diagnostic yield and cost of WES in comparison to traditional thrombophilia testing. Methods: Since January of 2014, we have been performing WES in patients with a personal and family history of VTE seen at Yale New Haven Hospital. Thus far, 18 such patients have had a complete WES analysis. Data regarding patient demographics, number and type of VTE events, family/surgical history, medical co-morbidities, and traditional laboratory testing for inherited thrombophilias was recorded. Costs of each test were determined based on the amount billed to insurance. WES focusing on 33 genes involved in thrombosis was performed and analyzed by the DNA Diagnostic Lab at the Yale School of Medicine. Positive WES testing was defined as identification of a pathogenic variant in a gene known to be associated with thrombophilia, found at a frequency consistent with frequency of the disease, and with evidence that the variant predisposes to thrombosis. Positive laboratory testing was defined as any test that led to an unequivocal diagnosis of Factor V Leiden, PT mutation, homozygous MTHFR mutation with hyperhomocysteinemia, or a deficiency in AT, PC, or PS. Results: All 18 patients (7 male, 11 female) were included in the final analysis. Median age at first VTE was 35.5 years (range, 14-78 years); median number of independent VTE events was 2 (range, 1-9). WES with our 33-gene thrombophilia panel was positive in 11 of 18 (61.1%) patients, while traditional laboratory testing was positive in only 2 of 16 (12.5%) cases (Table 1). There were no statistically significant differences in clinical characteristics between those patients with positive findings on WES versus those without. Identified variants included those in genes with well known roles in thrombosis (SERPINC1, PROS1, F5), and in genes with emerging data regarding thrombosis (HABP2, SERPINA10, SERPIND1). Two patients identified on WES as having PS deficiency, one with AT deficiency, and one with a non-Leiden Factor V mutation had laboratory testing that was either normal or uninterpretable. The total cost of WES at our institution was $1935.00; by comparison, among 16 patients who underwent laboratory testing, median cost of laboratory testing was $2892.70 (range, $406.90-$11419.80), and the cost of laboratory testing exceeded WES in 13 patients. Conclusions: WES using our 33-gene thrombophilia panel has higher diagnostic yield and is more cost effective than traditional thrombophilia testing. With increasing availability and declining cost, this thrombophilia gene panel has the potential to truly transform thrombophilia testing. Further investigation of the diagnostic power and phenotypic correlation of identified mutations is in progress. Table 1. Mutations detected by the 33 gene thrombophilia panel Gender Age (yrs) Lab testing result WES result M 40 Negative SERPINA10 (Q384R) heterozygous M 67 Negative SERPINC1 (S426W) heterozygous M 30 Negative PROS1 (Y234C) heterozygous F 34 Negative HABP2 (G508E) heterozygous F 56 APC resistance F5 (R506Q) heterozygous F 27 F2 20210 G>A heterozygous F2 20210G>A heterozygous; vWF P2063S heterozygous F 37 Negative SERPIND1 (R468C) heterozygous F 48 Negative F5 (T915S) heterozygous M 20 Negative PROS1 (P76L) heterozygous M 55 Negative SERPINA10 (21_23delCCT ) heterozygous F 78 Negative HABP2 (G534E) heterozygous F 49 Negative Negative F 41 Negative Negative M 32 Negative Negative F 64 Negative Negative M 42 Negative Negative F 51 Negative Negative F 28 Negative Negative Disclosures No relevant conflicts of interest to declare.

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Biasiolo, Alessandra, Michele Sandre, Stefania Ferro, Santina Quarta, Mariagrazia Ruvoletto, Gianmarco Villano, Cristian Turato, Maria Guido, Oriano Marin, and Patrizia Pontisso. "Epitope-Specific Anti-SerpinB3 Antibodies for SerpinB3 Recognition and Biological Activity Inhibition." Biomolecules 13, no. 5 (April 25, 2023): 739. http://dx.doi.org/10.3390/biom13050739.

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SerpinB3 is a serine protease inhibitor that plays a relevant role in disease progression and cancer by increasing fibrosis, cell proliferation, and invasion, besides conferring resistance to apoptosis. The mechanisms underlying these biological activities are not yet fully understood. The aim of this study was to generate antibodies directed against different SerpinB3 epitopes to better investigate their biological role. Five exposed epitopes were identified using the software DNASTAR Lasergene and the corresponding synthetic peptides were used for NZW rabbit immunization. Anti-P#2 and anti-P#4 antibodies were able to recognize both SerpinB3 and SerpinB4 by ELISA. Anti-P#5 antibody, produced against the reactive site loop of SerpinB3, showed the greatest specific reactivity for human SerpinB3. This antibody was able to recognize SerpinB3 at nuclear level, while anti-P#3 antibody recognized SerpinB3 only at cytoplasmic level, both by immunofluorescence and by immunohistochemistry. The biological activity of each antibody preparation was assessed in HepG2 cells overexpressing SerpinB3 and anti-P#5 antibody reduced proliferation by 12% cell and cell invasion by 75%, while trivial results were obtained with the other antibody preparations. These findings indicate that the reactive site loop of SerpinB3 is essential for the invasiveness features induced by this serpin and it could become a novel druggable target.

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Seo, Yu-Mi, Seok Hwang-Bo, Soo-Ah Im, Myungshin Kim, and Young-Ah Youn. "Predictive Value of Heat-Shock Protein Gene Expression on Severe Neonatal Hypoxic-Ischemic Encephalopathy." Diagnostics 12, no. 4 (April 13, 2022): 981. http://dx.doi.org/10.3390/diagnostics12040981.

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This study aims to evaluate significant gene expression in severe hypoxic ischemic encephalopathy (HIE) in newborns, which can be used as a predictable measure for high-risk HIE infants. The study prospectively recruited 77 inborn near-term or term HIE newborns between January 2018 and December 2020. We measured six different genes within 6 h of life among the HIE infants and compared the gene levels between the mild- and severe-HIE groups. Among these, 64 HIE infants (83.1%) did not receive therapeutic hypothermia (TH) because they were categorized as mild HIE, and the 13 remaining (16.9%) infants were categorized as ≥ moderate-HIE group and received TH. More abnormal MRI findings, seizure, and use of anti-convulsant were more found in the ≥ moderate = HIE group along with longer mechanical ventilation days and hospitalization. Heat-shock protein 70 family 1 A (HSPA1A) and serpin family H member 1 (SERPINH1) genes, which encode heat-shock protein (HSP) 70 and 47, respectively, were significantly elevated in the ≥ moderate-HIE, seizure, and abnormal MRI groups. HSP 70 and 47 were significantly elevated in the severe-HIE group, possibly playing protective roles in inhibiting exacerbated neuroinflammation and maintaining a cellular homeostasis. At 18–24 months, ≥ moderate-HIE group manifested a significant language delay.

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