Journal articles: 'SERPINI1'

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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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Han, Sha, Fei Fei, Shaoyang Sun, Dongyang Zhang, Qiang Dong, Xu Wang, and Liang Wang. "Increased anxiety was found in serpini1 knockout zebrafish larval." Biochemical and Biophysical Research Communications 534 (January 2021): 1013–19. http://dx.doi.org/10.1016/j.bbrc.2020.10.048.

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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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Matsuda, Yasufumi, Koh Miura, Junko Yamane, Hiroshi Shima, Wataru Fujibuchi, Kazuyuki Ishida, Fumiyoshi Fujishima, et al. "SERPINI1 regulates epithelial–mesenchymal transition in an orthotopic implantation model of colorectal cancer." Cancer Science 107, no. 5 (March 28, 2016): 619–28. http://dx.doi.org/10.1111/cas.12909.

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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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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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Kara, Bülent, Cansu Eğilmez Sarıkaya, Yunus Emre Bayrak, Ayfer Sakarya Güneş, Mesut Güngör, and Gözde Yeşil. "Early-onset rapidly progressive myoclonic epilepsy associated with G392R likely pathogenic variant in SERPINI1." Seizure 80 (August 2020): 181–82. http://dx.doi.org/10.1016/j.seizure.2020.06.022.

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Yamanaka, Sumitaka, Alexandru V. Olaru, Fangmei An, Delgermaa Luvsanjav, Zhe Jin, Rachana Agarwal, Ciprian Tomuleasa, et al. "MicroRNA-21 inhibits Serpini1, a gene with novel tumour suppressive effects in gastric cancer." Digestive and Liver Disease 44, no. 7 (July 2012): 589–96. http://dx.doi.org/10.1016/j.dld.2012.02.016.

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Chen, Ping-Yen, Wun-Shaing W. Chang, Yiu-Kay Lai, and Cheng-Wen Wu. "c-Myc regulates the coordinated transcription of brain disease-related PDCD10–SERPINI1 bidirectional gene pair." Molecular and Cellular Neuroscience 42, no. 1 (August 2009): 23–32. http://dx.doi.org/10.1016/j.mcn.2009.05.001.

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Tjärnlund-Wolf, A., S. Olsson, K. Jood, C. Blomstrand, and C. Jern. "No evidence for an association between genetic variation at the SERPINI1 locus and ischemic stroke." Journal of Neurology 258, no. 10 (April 13, 2011): 1885–87. http://dx.doi.org/10.1007/s00415-011-6022-0.

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Nagahashi, Kotomi, Katsuhiro Takano, Katsue Suzuki-Inoue, Naohiro Kanayama, Kazuo Umemura, Tetsumei Urano, and Takayuki Iwaki. "Mutation in a highly conserved glycine residue in strand 5B of plasminogen activator inhibitor 1 causes polymerisation." Thrombosis and Haemostasis 117, no. 05 (2017): 860–69. http://dx.doi.org/10.1160/th16-07-0572.

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SummarySerpinopathy is characterised as abnormal accumulation of serine protease inhibitors (SERPINs) in cells and results in clinical symptoms owing to lack of SERPIN function or excessive accumulation of abnormal SERPIN. We recently identified a patient with functional deficiency of plasminogen activator inhibitor-1 (PAI-1), a member of the SERPIN superfamily. The patient exhibited life-threatening bleeding tendencies, which have also been observed in patients with a complete deficiency in PAI-1. Sequence analysis revealed a homozygous singlenucleotide substitution from guanine to cytosine at exon 9, which changed amino acid residue 397 from glycine to arginine (c.1189G>C; p.Gly397Arg). This glycine was located in strand 5B and was well conserved in other serpins. The mutant PAI-1 was polymerised in the cells, interfering with PAI-1 secretion. The corresponding mutations in SERPINC1 (anti-thrombin III) at position 456 (Gly456Arg) and SERPINI1 (neuroserpin) at position 392 (Gly392Glu) caused an anti-thrombin deficiency and severe dementia due to intracellular retention of the polymers. Glycine is the smallest amino acid, and these mutated amino acids were larger and charged. To determine which factors were important, further mutagenesis of PAI-1 was performed. Although the G397A, C, I, L, S, T, and V were secreted, the G397D, E, F, H, K, M, N, P, Q, W, and Y were not secreted. The results revealed that the size was likely triggered by the polymerisation of SEPRINs at this position. Structural analyses of this mutated PAI-1 would be useful to develop a novel PAI-1 inhibitor, which may be applicable in the context of several pathological states.

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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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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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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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Vapore, Valentina, Corrado Mazzaglia, Diego Sibilia, Mara Del Vecchio, Gernot Fruhmann, Marta Valenti, Elena Miranda, Teresa Rinaldi, Joris Winderickx, and Cristina Mazzoni. "Neuroserpin Inclusion Bodies in a FENIB Yeast Model." Microorganisms 9, no. 7 (July 13, 2021): 1498. http://dx.doi.org/10.3390/microorganisms9071498.

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FENIB (familial encephalopathy with neuroserpin inclusion bodies) is a human monogenic disease caused by point mutations in the SERPINI1 gene, characterized by the intracellular deposition of polymers of neuroserpin (NS), which leads to proteotoxicity and cell death. Despite the different cell and animal models developed thus far, the exact mechanism of cell toxicity elicited by NS polymers remains unclear. Here, we report that human wild-type NS and the polymerogenic variant G392E NS form protein aggregates mainly localized within the endoplasmic reticulum (ER) when expressed in the yeast S. cerevisiae. The expression of NS in yeast delayed the exit from the lag phase, suggesting that NS inclusions cause cellular stress. The cells also showed a higher resistance following mild oxidative stress treatments when compared to control cells. Furthermore, the expression of NS in a pro-apoptotic mutant strain-induced cell death during aging. Overall, these data recapitulate phenotypes observed in mammalian cells, thereby validating S. cerevisiae as a model for FENIB.

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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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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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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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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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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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Mo, Yuqing, Kan Zhang, Yuchen Feng, Lingling Yi, Yuxia Liang, Wenliang Wu, Jianping Zhao, et al. "Epithelial SERPINB10, a novel marker of airway eosinophilia in asthma, contributes to allergic airway inflammation." American Journal of Physiology-Lung Cellular and Molecular Physiology 316, no. 1 (January 1, 2019): L245—L254. http://dx.doi.org/10.1152/ajplung.00362.2017.

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Serine peptidase inhibitor, clade B, member 10 (SERPINB10) expression is increased in IL-13-stimulated human bronchial epithelial cells and in a murine model of allergic airway inflammation. However, the role of SERPINB10 in asthma remains unknown. We examined the association between epithelial SERPINB10 expression and airway eosinophilia in subjects with asthma and the role of Serpinb10 in allergic airway inflammation in an animal model. Epithelial SERPINB10 mRNA and protein expression were markedly increased in subjects with asthma ( n = 60) compared with healthy controls ( n = 25). Epithelial SERPINB10 mRNA levels were significantly correlated with airway hyperresponsiveness (AHR) and three parameters reflecting airway eosinophilia including the percentage of sputum eosinophils, the number of eosinophils in bronchial submucosa, and fraction of exhaled nitric oxide in subjects with asthma. Moreover, epithelial SERPINB10 expression was strongly correlated with the epithelial gene signature ( CLCA1, POSTN, and SERPINB2) for type 2 status. In normal human bronchial epithelial cells cultured at air-liquid interface, knockdown of SERPINB10 suppressed IL-13-stimulated periostin (encoded by POSTN) and CCL26 (eotaxin-3) expression by inhibiting the activation of p38 MAPK. Epithelial CCL26 mRNA levels were correlated with SERPINB10 expression in subjects with asthma. Airway knockdown of Serpinb10 alleviated AHR, airway eosinophilia and the expression of periostin and Ccl26 in a murine model of allergic airway disease. Taken together, epithelial SERPINB10 is a novel marker for airway eosinophilia in asthma. Epithelial SERPINB10 contributes to allergic airway eosinophilic inflammation, at least in part, by regulating the expression of periostin and CCL26.

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Borel, Florie, Huaming Sun, Marina Zieger, Andrew Cox, Brynn Cardozo, Weiying Li, Gabriella Oliveira, et al. "Editing out five Serpina1 paralogs to create a mouse model of genetic emphysema." Proceedings of the National Academy of Sciences 115, no. 11 (February 16, 2018): 2788–93. http://dx.doi.org/10.1073/pnas.1713689115.

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Chronic obstructive pulmonary disease affects 10% of the worldwide population, and the leading genetic cause is α-1 antitrypsin (AAT) deficiency. Due to the complexity of the murine locus, which includes up to six Serpina1 paralogs, no genetic animal model of the disease has been successfully generated until now. Here we create a quintuple Serpina1a–e knockout using CRISPR/Cas9-mediated genome editing. The phenotype recapitulates the human disease phenotype, i.e., absence of hepatic and circulating AAT translates functionally to a reduced capacity to inhibit neutrophil elastase. With age, Serpina1 null mice develop emphysema spontaneously, which can be induced in younger mice by a lipopolysaccharide challenge. This mouse models not only AAT deficiency but also emphysema and is a relevant genetic model and not one based on developmental impairment of alveolarization or elastase administration. We anticipate that this unique model will be highly relevant not only to the preclinical development of therapeutics for AAT deficiency, but also to emphysema and smoking research.

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Riaz, Nadeem, Jonathan J. Havel, Sviatoslav M. Kendall, Vladimir Makarov, Logan A. Walsh, Alexis Desrichard, Nils Weinhold, and Timothy A. Chan. "Recurrent SERPINB3 and SERPINB4 mutations in patients who respond to anti-CTLA4 immunotherapy." Nature Genetics 48, no. 11 (September 26, 2016): 1327–29. http://dx.doi.org/10.1038/ng.3677.

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Biasiolo, Alessandra, Natascia Tono, Mariagrazia Ruvoletto, Santina Quarta, Cristian Turato, Gianmarco Villano, Luca Beneduce, et al. "IgM-Linked SerpinB3 and SerpinB4 in Sera of Patients with Chronic Liver Disease." PLoS ONE 7, no. 7 (July 13, 2012): e40658. http://dx.doi.org/10.1371/journal.pone.0040658.

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Scarff, Katrina L., Kheng S. Ung, Harshal Nandurkar, Peter J. Crack, Catherina H. Bird, and Phillip I. Bird. "Targeted Disruption of SPI3/Serpinb6 Does Not Result in Developmental or Growth Defects, Leukocyte Dysfunction, or Susceptibility to Stroke." Molecular and Cellular Biology 24, no. 9 (May 1, 2004): 4075–82. http://dx.doi.org/10.1128/mcb.24.9.4075-4082.2004.

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ABSTRACT Protease inhibitor 6 (PI-6/SERPINB6) is a widely expressed nucleocytoplasmic serpin. It inhibits granulocyte cathepsin G and neuronal neuropsin, and it is thought to protect cells from death caused by ectopic release or internalization of protease during stress such as infection or cerebral ischemia. To probe the biological functions of PI-6, we generated mice lacking its ortholog (SPI3/Serpinb6). SPI3-deficient mice developed normally and were fertile, and no abnormal pathology or increased sensitivity to cerebral ischemia was observed. There were no perturbations in leukocyte development or numbers, and recruitment of leukocytes to the peritoneal cavity was normal. SPI3-deficient mice were equally susceptible as wild-type mice to systemic Candida albicans infection, although there was a slight decrease in the ability of neutrophils from SPI3-deficient mice to kill C. albicans in vitro. Increased levels of a related inhibitor Serpinb1 (monocyte/neutrophil elastase inhibitor) in the tissues of targeted mice suggests that compensation by other serpins reduces the impact of SPI3 deficiency in these animals and may explain the lack of a more obvious phenotype.

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Lanza, Giuseppe, Francesco Calì, Mirella Vinci, Filomena Irene Ilaria Cosentino, Mariangela Tripodi, Rosario Sebastiano Spada, Mariagiovanna Cantone, Rita Bella, Teresa Mattina, and Raffaele Ferri. "A Customized Next-Generation Sequencing-Based Panel to Identify Novel Genetic Variants in Dementing Disorders: A Pilot Study." Neural Plasticity 2020 (August 18, 2020): 1–10. http://dx.doi.org/10.1155/2020/8078103.

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Purpose. The advancements in the next-generation sequencing (NGS) techniques have allowed for rapid, efficient, and cost-time-effective genetic variant detection. However, in both clinical practice and research setting, sequencing is still often limited to the use of gene panels clinically targeted on the genes underlying the disease of interest. Methods. We performed a neurogenetic study through an ad hoc NGS-based custom sequencing gene panel in order to screen 16 genes in 8 patients with different types of degenerative cognitive disorders (Alzheimer’s disease, mild cognitive impairment, frontotemporal dementia, and dementia associated with Parkinson’s disease). The study protocol was based on previous evidence showing a high sensitivity and specificity of the technique even when the panel is limited to some hotspot exons. Results. We found variants of the TREM2 and APP genes in three patients; these have been previously identified as pathogenic or likely pathogenic and, therefore, considered “disease causing.” In the remaining subjects, the pathogenicity was evaluated according to the guidelines of the American College of Medical Genetics (ACMG). In one patient, the p.R205W variant in the CHMP2B gene was found to be likely pathogenic of the disease. A variant in the CSF1R and SERPINI1 genes found in two patients was classified as benign, whereas the other two (in the GRN and APP genes) were classified as likely pathogenic according to the ACMG. Conclusions. Notwithstanding the preliminary value of this study, some rare genetic variants with a probable disease association were detected. Although future application of NGS-based sensors and further replication of these experimental data are needed, this approach seems to offer promising translational perspectives in the diagnosis and management of a wide range of neurodegenerative disorders.

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Utge, Siddheshwar, Katri Räikkönen, Eero Kajantie, Jari Lipsanen, Sture Andersson, Timo Strandberg, Rebecca M. Reynolds, Johan G. Eriksson, and Jari Lahti. "Polygenic risk score of SERPINA6 / SERPINA1 associates with diurnal and stress-induced HPA axis activity in children." Psychoneuroendocrinology 93 (July 2018): 1–7. http://dx.doi.org/10.1016/j.psyneuen.2018.04.009.

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Granados-Montiel, Julio, Monica Cruz-Lemini, Claudia Rangel-Escareño, Gabriela Martinez-Nava, Carlos Landa-Solis, Ricardo Gomez-Garcia, Alberto Lopez-Reyes, Alejandro Espinosa-Gutierrez, and Clemente Ibarra. "SERPINA9 and SERPINB2: Novel Cartilage Lineage Differentiation Markers of Human Mesenchymal Stem Cells with Kartogenin." CARTILAGE 12, no. 1 (October 29, 2018): 102–11. http://dx.doi.org/10.1177/1947603518809403.

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Objective Human mesenchymal stem cells (hMSCs) are a promising source for regenerative medicine, especially mesodermal lineages. Clinical applications require an understanding of the mechanisms for transcriptional control to maintain the desired cell type. The aim of this study was to identify novel markers for differentiation of hMSCs into bone or cartilage with the use of Kartogenin, by RNA analysis using microarray technology, and explore the role of RhoA-Rho associated protein kinase (ROCK) inhibition in these. Methods Commercial human bone marrow derived primary mesenchymal stem cells were purchased from ATCC. Cells were differentiated in vitro in 2-dimensional cultures using Kartogenin as the main cartilage inducer and bone morphogenetic protein 2 for bone differentiation; cells were cultured with and without ROCK inhibitor Y-27632. After 21 days of culture, whole RNA was extracted and analyzed via Affimetrix microarrays. The most significant hits were validated by quantitative polymerase chain reaction. Results We found a total of 1,757 genes that were either up- or downregulated on differentiation, when compared to P1 hMSC (control) at day 0 of differentiation. Two members of the Serpin superfamily, SERPINA9 and SERPINB2, were significantly upregulated in the cartilage groups, whereas they were unchanged in the bone groups with and without ROCK inhibition. Conclusions SERPINA9 and SERPINB2 are novel differentiation markers, and molecular regulator candidates for hMSC lineage commitment toward bone and cartilage, providing a new tool for regenerative medicine. Our study highlights the roles of these 2 genes, with significant upregulation of both in cell cultures stimulated with Kartogenin.

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Bolton, Jennifer L., Caroline Hayward, Nese Direk, John G. Lewis, Geoffrey L. Hammond, Lesley A. Hill, Anna Anderson, et al. "Genome Wide Association Identifies Common Variants at the SERPINA6/SERPINA1 Locus Influencing Plasma Cortisol and Corticosteroid Binding Globulin." PLoS Genetics 10, no. 7 (July 10, 2014): e1004474. http://dx.doi.org/10.1371/journal.pgen.1004474.

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Qu, Xiaolu, Shuangshuang Guo, Leyan Yan, Huanxi Zhu, Hui Li, and Zhendan Shi. "TNFα-Erk1/2 signaling pathway-regulated SerpinE1 and SerpinB2 are involved in lipopolysaccharide-induced porcine granulosa cell proliferation." Cellular Signalling 73 (September 2020): 109702. http://dx.doi.org/10.1016/j.cellsig.2020.109702.

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Odet, Fanny, Adélie Verot, and Brigitte Le Magueresse-Battistoni. "The Mouse Testis Is the Source of Various Serine Proteases and Serine Proteinase Inhibitors (SERPINs): Serine Proteases and SERPINs Identified in Leydig Cells Are under Gonadotropin Regulation." Endocrinology 147, no. 9 (September 1, 2006): 4374–83. http://dx.doi.org/10.1210/en.2006-0484.

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The occurrence of various serine proteinases and serine proteinases inhibitors (SERPINs) was investigated by RT-PCR in whole testes of 1-, 3-, and 8-wk-old mice in crude and enriched germ cell fractions, mouse Leydig tumor cells (mLTC-1), and primary cultures of 3- and 8-wk-old enriched fractions of Leydig cells and 3-wk-old Sertoli cells. New members were identified in the testis protease repertoire. Within the Leydig repertoire, a PCR product was found for plasminogen activators urokinase plasminogen activator (uPA) and tissue plasminogen activator (8-wk-old cells), matriptase-2 (mLTC-1), kallikrein-21, SERPINA5, SERPINB2 (primary cultures), and serine peptidase inhibitor Kunitz type 2 (SPINT2). The gonadotropin regulation was explored by semiquantitative RT-PCR, using steroidogenic acute regulatory protein (StAR) as a positive control. Matriptase-2, kallikrein-21, SPINT2, and SERPINA5 were down-regulated, whereas uPA and its receptor were up-regulated by human chorionic gonadotropin (hCG) via cAMP in the mLTC-1 cells. Positive effects were observed transiently after 1–8 h of hCG exposure, and negative effects, first evidenced after 6 h, lasted 48 h. The hCG-induced effects were confirmed in primary cultures. In addition, SERPINB2 was augmented by hCG in primary cultures. Addition of either trypsin or protease inhibitors did not alter the hCG-induced surge of StAR. Because hCG regulated proteases and SERPINs (whereas testosterone did not), it could alter the proteolytic balance of Leydig cells and consequently the metabolism of extracellular matrix components. Therefore, even though a direct interplay between the early hCG-induced surge of uPA and StAR is unlikely, our data together with the literature suggest that extracellular matrix proteins alter Leydig cell steroidogenesis.

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Lee, Mingyung, Hyesun Park, Jung Min Heo, Ho Jun Choi, and Seongwon Seo. "Multi-tissue transcriptomic analysis reveals that L-methionine supplementation maintains the physiological homeostasis of broiler chickens than D-methionine under acute heat stress." PLOS ONE 16, no. 1 (January 27, 2021): e0246063. http://dx.doi.org/10.1371/journal.pone.0246063.

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The objective of this study was to compare the effects of supplementation with two methionine isoforms, L-methionine (L-Met) or D-methionine (D-Met), on transcriptome expression in broiler chickens under acute heat stress. A total of 240 one-day-old chicks were randomly assigned to one of four treatments in a 2 × 2 factorial arrangement: thermo-neutral vs. acute heat-stress and L-Met vs. D-Met supplementation. On day 14, the heat-stressed group was exposed to 32°C for 5 h, while the others remained at 25°C. Six chicks were randomly selected per treatment and total RNA was isolated from whole blood, ileum, and liver tissues. Two RNA samples from each tissue of each treatment group were randomly selected and pooled in equal amounts. A total of 1.87 billion raw reads obtained from 36 samples (four treatments × three tissues × three composited replicates) were mapped to the reference genome build (Gallus_gallus-5.0) and used to identify differentially expressed genes (DEGs) using DESeq2. Functional enrichment of DEGs was tested using DAVID. Comparing the two isoforms of supplemented methionine, two, three, and ten genes were differentially expressed (> 1 or < -1 log2 fold change) in whole blood, ileum, and liver, respectively. A total of 38, 71, and 16 genes were differentially expressed in response to the interaction between heat stress and Met isoforms in the blood, ileum, and liver, respectively. Three-tissue-specific DEGs were functionally enriched for regulation of cholesterol homeostasis and metabolism, glucose metabolism, and vascular patterning. Chicks fed with L-Met had lower immune (e.g., IL4I1 and SERPINI1) and intestinal angiogenic responses (e.g., FLT1 and FGD5), and stable glucose and lipid metabolism (e.g., PCK1 and LDLR) under heat stress conditions. In conclusion, unlike D-Met, L-Met supplementation seems to help maintain physiological homeostasis and enhances cellular defense systems against external stresses like high environmental temperature.

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Amati, Francesco, Andrea Gramegna, Martina Contarini, Anna Stainer, Cristina Curcio, Stefano Aliberti, Angelo Guido Corsico, and Francesco Blasi. "Genetic and Serum Screening for Alpha-1-Antitrypsin Deficiency in Adult Patients with Cystic Fibrosis: A Single-Center Experience." Biomedicines 10, no. 12 (December 14, 2022): 3248. http://dx.doi.org/10.3390/biomedicines10123248.

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Cystic fibrosis (CF) and alpha-1 antitrypsin (AAT) deficiency are two of the commonest genetic diseases affecting the Caucasian population. Neutrophil-mediated inflammation due to protease–antiprotease imbalance leads to progressive pulmonary involvement in both diseases. The aim of this study was to investigate the prevalence of AAT deficiency in CF adults. A prospective study enrolling CF adults was conducted at the Adult CF Center based in Milan from January 2018 to March 2019. Patients were tested for AAT serum protein quantification and expanded genotyping characterization of SERPINA1 during clinical stability. Genotyping characterization of SERPIN1 was compared to a control population of 2848 Caucasian individuals with the same geographical origin and similar demographic characteristics. Among 173 patients included in the study, the prevalence of AAT deficiency was 0. Genotype analysis was piMM in 166 (94.9%) patients and piMS in 9 patients (5.1%), respectively. No differences in terms of genotype characterization were found between the CF population and the control population. These data show that AAT deficiency is not common among adults with CF.

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Burgener, Sabrina Sofia, Nathan Georges François Leborgne, Scott J. Snipas, Guy S. Salvesen, Phillip Ian Bird, and Charaf Benarafa. "Cathepsin G Inhibition by Serpinb1 and Serpinb6 Prevents Programmed Necrosis in Neutrophils and Monocytes and Reduces GSDMD-Driven Inflammation." Cell Reports 27, no. 12 (June 2019): 3646–56. http://dx.doi.org/10.1016/j.celrep.2019.05.065.

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Quan, Qingli, Xinxin Xiong, Shanyun Wu, and Meixing Yu. "Identification of Autophagy-Related Prognostic Signature and Analysis of Immune Cell Infiltration in Low-Grade Gliomas." BioMed Research International 2021 (November 8, 2021): 1–24. http://dx.doi.org/10.1155/2021/7918693.

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Autophagy plays an important role in cancer. Many studies have demonstrated that autophagy-related genes (ARGs) can act as a prognostic signature for some cancers, but little has been known in low-grade gliomas (LGG). In our study, we aimed to establish a prognostical model based on ARGs and find prognostic risk-related key genes in LGG. In the present study, a prognostic signature was constructed based on a total of 8 ARGs (MAPK8IP1, EEF2, GRID2, BIRC5, DLC1, NAMPT, GRID1, and TP73). It was revealed that the higher the risk score, the worse was the prognosis. Time-dependent ROC analysis showed that the risk score could precisely predict the prognosis of LGG patients. Additionally, four key genes (TGFβ2, SERPING1, SERPINE1, and TIMP1) were identified and found significantly associated with OS of LGG patients. Besides, they were also discovered to be strongly related to six types of immune cells which infiltrated in LGG tumor. Taken together, the present study demonstrated the promising potential of the ARG risk score formula as an independent factor for LGG prediction. It also provided the autophagy-related signature of prognosis and potential therapeutic targets for the treatment of LGG.

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Zhang, Fabin, Chunhui Hu, Shilei Cheng, Shulin Wang, Bin Li, Deping Cao, Haining Fan, Ruchong Pan, Mei Yang, and Yanhui Xu. "The Investigation of the Effect and Mechanism of Sophora moorcroftiana Alkaloids in Combination with Albendazole on Echinococcosis in an Experimental Rats Model." Evidence-Based Complementary and Alternative Medicine 2018 (2018): 1–10. http://dx.doi.org/10.1155/2018/3523126.

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Echinococcosis is a worldwide anthropozoonosis which is highly endemic over large animal husbandry areas in northwestern China. The current clinical therapeutic medicine against echinococcosis is albendazole, although it caused serious side effects in patients. The component in traditional Chinese herb medicine, Sophora moorcroftiana alkaloids (SA), is thought to be a potential drug to treat echinococcosis. In order to explore the effect and mechanism of SA treatment against echinococcosis, we established animal echinococcosis model and treated rats with albendazole alone, alkaloids alone, and combined therapy. The combined treatment showed effective inhibition against parasite infection due to induction of host response and alleviated liver injury; meanwhile albendazole caused serious liver problem. The proteomics study revealed that the combined therapy might induce complement activation through C3, C4, C5, SERPINA1, and SERPINC1 proteins and cell adhesion by ANXA2, EZR, YWHAB, HSP90AN1, and PRKAR2A proteins, while albendazole treatment could induce liver injury through CRYAB, YWHAZ, SLC25A24, and HSPA1B proteins that were involved in cell death. In all, we consider that the combinational treatment displayed better therapeutic effects against liver echinococcosis as well as alleviated liver injury, which could be considered as an effective strategy to treat echinococcosis clinically.

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Ou, Junwen, Qiulin Liao, Yanping Du, Wentao Xi, Qiong Meng, Kexin Li, Qichun Cai, et al. "P7-4 The SERPINB7, TMEM158, and SERPINE1 signature as predictor of prognosis in patients with NSCLC after vitamin C treatment." Annals of Oncology 33 (July 2022): S515. http://dx.doi.org/10.1016/j.annonc.2022.05.240.

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Chen, Shujia, Yuqiao Li, Yinghui Zhu, Jiayue Fei, Liaoyuan Song, Guoyan Sun, Lianyi Guo, and Xiaofei Li. "SERPINE1 Overexpression Promotes Malignant Progression and Poor Prognosis of Gastric Cancer." Journal of Oncology 2022 (January 29, 2022): 1–17. http://dx.doi.org/10.1155/2022/2647825.

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The serine protease inhibitor clade E member 1 (SERPINE1) is a major inhibitor of tissue plasminogen activator and urokinase, and has been implicated in the development and progression of a variety of tumors. In this study, mRNA microarray and TCGA database were used to comprehensively analyze the upregulation of SERPINE1 in gastric cancer (GC) tissues compared with the normal stomach tissues. Kaplan-Meier results confirmed that patients with high SERPINE1 expression exhibited worse overall survival and disease-free survival. In addition, cell proliferation, cell scratches, transwell migration and invasion assay showed that SERPINE1 knockdown inhibited the proliferation, migration and invasion of GC ells. Western blot showed that the expression of VEGF and IL-6 was significantly upregulated after overexpression of SERPINE1. Meanwhile, SERPINE1 was positively correlated with the level of immune infiltration using the online analysis tools TISIDB and TIMER. And SERPINE1 expression increased with the increase of malignancy of GC which were detected by Immunohistochemistry. Finally, tumorigenesis experiments in nude mice further demonstrated that SERPINE1 could promote the occurrence and development of GC, while deletion of SERPINE1 inhibited the progression of GC. In summary, SERPINE1 was highly expressed in GC tissues, and SERPINE1 was helpful for differential diagnosis of pathological grade of gastric mucosal lesions. SERPINE1 might regulate the expression of VEGF and IL-6 through the VEGF signaling pathway and JAK-STAT3 inflammatory signaling pathway, thus ultimately affecting the invasion and migration of GC cells.

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Xu, Xia, Hongchao Wang, Haijun Li, Xiaopei Cui, and Hongyu Zhang. "SERPINE1 -844 and -675 polymorphisms and chronic obstructive pulmonary disease in a Chinese Han population." Journal of International Medical Research 44, no. 6 (November 18, 2016): 1292–301. http://dx.doi.org/10.1177/0300060516664270.

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Objective To investigate the association between serpin family E member 1 ( SERPINE1) -844 A/G and -675 4G/5G polymorphisms and chronic obstructive pulmonary disease (COPD) in a Chinese Han population. Method SERPINE1 -844 A/G and -675 4G/5G polymorphisms were assessed by polymerase chain reaction-restriction fragment length polymorphism sequencing of genomic DNA from patients with COPD and healthy smoking controls. Results Out of 140 patients with COPD and 100 controls, all SERPINE1 -844 and -675 polymorphisms were in Hardy-Weinberg equilibrium. Differences in SERPINE1 -675 4G and 5G allele frequencies were statistically significant between the COPD and control groups (odds ratio [OR] 1.45, 95% confidence interval [CI] 1.00, 2.09), but there was no significant between-group difference in SERPINE1 -844 A and G allele frequencies. The SERPINE1 -675 4G/4G genotype was associated with COPD (OR 1.87, 95% CI 1.06, 3.32 [binary logistic regression]). Haplotype analysis showed that COPD was associated with SERPINE1 -844G/4G (OR 2.11, 95% CI 1.32, 3.38) and SERPINE1 -844G/5G (OR 0.66, 95% CI 0.45, 0.95). Conclusion The SERPINE1 -675 polymorphism, but not SERPINE1 -844 polymorphism, was associated with susceptibility to COPD in a Chinese Han population.

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Benarafa, Charaf, and Mathias Baumann. "SerpinB1 inhibition of cathepsin G is critical for neutrophil survival and the maintenance of the bone marrow reserve of mature neutrophils in vivo (110.14)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 110.14. http://dx.doi.org/10.4049/jimmunol.186.supp.110.14.

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Abstract The bone marrow reserve of neutrophils is required for a rapid and effective mobilization to infected tissues. We recently reported that this reserve is considerably reduced in serpinB1-/- mice due to a survival defect of mature neutrophils. SerpinB1 inhibits the three neutrophil serine proteases (NSPs): elastase (NE), cathepsin G (CG) and proteinase-3 and is expressed at high levels in neutrophils but also in non-hematopoietic cells. Here, we found that, in bone marrow chimera, serpinB1 deficiency in hematopoietic cells was necessary and sufficient to reproduce the bone marrow neutropenia observed in serpinB1-/- mice. In addition, when irradiated mice were reconstituted with a 1:1 mixture of serpinB1-/- and wild type bone marrow cells, only a small percentage of the mature neutrophils were from the serpinB1-/- donor, whereas B cells of the two genotypes were found in equal proportions. Mice lacking serpinB1 as well as active NSPs due to deficiency in dipeptidyl peptidase I (serpinB1-/-.dppi-/-) had a normal neutrophil reserve indicating that one or more NSPs was involved in the bone marrow defect. Deficiency in CG alone, but not NE, was sufficient to fully restore a normal number of bone marrow neutrophils in serpinB1-/- mice. Collectively, these findings demonstrate that serpinB1 protects the neutrophil reserve in a cell autonomous manner and indicate a novel cell death pathway in neutrophils mediated by serine protease cathepsin G and regulated by serpinB1.

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Benarafa, Charaf, and Mathias Baumann. "The bone marrow neutrophil reserve is regulated by serpinB1 and cathepsin G through a cell autonomous and caspase-independent death pathway (172.32)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 172.32. http://dx.doi.org/10.4049/jimmunol.188.supp.172.32.

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Abstract The bone marrow (BM) neutrophil reserve is a large pool of mature neutrophils that can be rapidly mobilized to the circulation and recruited to tissues in response to danger signals. We have previously shown that serpinB1-/- mature neutrophils have a survival defect that leads to a considerable reduction of the BM reserve and failure to clear bacterial infection. SerpinB1 is one of the best inhibitors of neutrophil serine proteases including elastase (NE) and cathepsin G (CG). Here, BM chimera showed that serpinB1 deficiency in hematopoietic cells was necessary and sufficient to reproduce the bone marrow neutropenia of serpinB1-/- mice. We found that CG, but not NE, was responsible for the BM neutropenia of serpinB1-/- mice. Mice deficient in both CG and serpinB1 had a normal neutrophil reserve, whereas NE-deficiency did not rescue the BM defect of serpinB1-/- mice. Neutrophil survival was increased by pan-caspase inhibitor Q-VD-OPh in both wild-type and serpinB1-/- neutrophils in vitro compared to untreated cells. However, survival was significantly lower in serpinB1-/- neutrophils (35%) vs. wild type (80%) after 72hr. This survival defect in vitro was rescued by CG deficiency. Furthermore, neither transgenic over expression of anti-apoptotic factor BCL-2 nor G-CSF treatment of serpinB1-/- mice rescued CG-mediated neutrophil death. We conclude that CG and serpinB1 regulate neutrophil survival through a proteolytic process distinct from classical apoptotic pathways.

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Liu, Wenjun, Min Du, Hongping Wan, Hao Yang, Xiaorong Deng, Yu Chen, and Qian Zhang. "Serpin family A member 1 is an oncogene in glioma and its translation is enhanced by NAD(P)H quinone dehydrogenase 1 through RNA-binding activity." Open Medicine 17, no. 1 (January 1, 2022): 1645–54. http://dx.doi.org/10.1515/med-2022-0572.

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Abstract Serpin family A member 1 (SERPINA1) is expressed abundantly in gliomas and can predict unfavorable prognosis of patients with glioma. Studies have shown that nicotinamide adenine dinucleotide phosphate quinone dehydrogenase 1 (NQO1) can promote the proliferation of glioblastoma multiforme cells and enhance the expression of SERPINA1, but its effects on glioma cells remain unknown. In this study, we explored the functions of SERPINA1 in glioma tumorigenesis in vitro and then investigated whether NQO1 affects the protein expression of SERPINA1 and its mRNA level. The results showed that the translation of SERPINA1 was suppressed while its mRNA level had no significant changes under the condition of NQO1 silencing. Luciferase reporter assay and biotin pull-down assay further indicated that NQO1 bond with SERPINA1 3′ untranslated region. miR-1321 was also identified to target SERPINA1, repressing its mRNA and protein levels. SERPINA1 and NQO1 promoted glioma cell proliferation and suppressed cell apoptosis. Moreover, SERPINA1 rescued the effects of sh-NQO1 in glioma cell malignant phenotypes. In conclusion, our findings showed that oncogene NQO1 and antioncogene miR-1321 bind to oncogene SERPINA1 to affect proliferation and apoptosis of glioma cells, which can bring new solution of antitumor treatments for glioma in the future.

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Bukosza, Eva Nora, Christoph Kornauth, Karin Hummel, Helga Schachner, Nicole Huttary, Sigurd Krieger, Katharina Nöbauer, et al. "ECM Characterization Reveals a Massive Activation of Acute Phase Response during FSGS." International Journal of Molecular Sciences 21, no. 6 (March 18, 2020): 2095. http://dx.doi.org/10.3390/ijms21062095.

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The glomerular basement membrane (GBM) and extra-cellular matrix (ECM) are essential to maintain a functional interaction between the glomerular podocytes and the fenestrated endothelial cells in the formation of the slit diaphragm for the filtration of blood. Dysregulation of ECM homeostasis can cause Focal segmental glomerulosclerosis (FSGS). Despite this central role, alterations in ECM composition during FSGS have not been analyzed in detail yet. Here, we characterized the ECM proteome changes in miR-193a-overexpressing mice, which suffer from FSGS due to suppression of Wilms’ tumor 1 (WT1). By mass spectrometry we identified a massive activation of the acute phase response, especially the complement and fibrinogen pathways. Several protease inhibitors (ITIH1, SERPINA1, SERPINA3) were also strongly increased. Complementary analysis of RNA expression data from both miR-193a mice and human FSGS patients identified additional candidate genes also mainly involved in the acute phase response. In total, we identified more than 60 dysregulated, ECM-associated genes with potential relevance for FSGS progression. Our comprehensive analysis of a murine FSGS model and translational comparison with human data offers novel targets for FSGS therapy.

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Starodubtseva, Natalia, Natalia Nizyaeva, Oleg Baev, Anna Bugrova, Masara Gapaeva, Kamilla Muminova, Alexey Kononikhin, Vladimir Frankevich, Eugene Nikolaev, and Gennady Sukhikh. "SERPINA1 Peptides in Urine as A Potential Marker of Preeclampsia Severity." International Journal of Molecular Sciences 21, no. 3 (January 30, 2020): 914. http://dx.doi.org/10.3390/ijms21030914.

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Preeclampsia (PE) is a multisystem disorder associated with pregnancy and its frequency varies from 5 to 20 percent of pregnancies. Although a number of preeclampsia studies have been carried out, there is no consensus about disease etiology and pathogenesis so far. Peptides of SERPINA1 (α1-antitrypsin) in urine remain one of the most promising peptide markers of PE. In this study the diagnostic potential of urinary α1-antitrypsin peptides in PE was evaluated. The urinary peptidome composition of 79 pregnant women with preeclampsia (PE), chronic arterial hypertension (CAH), and a control group was investigated. Mann–Whitney U-test (p < 0.05) revealed seven PE specific SERPINA1 peptides demonstrating 52% sensitivity and 100% specificity. SERPINA1 in urine has been associated with the most severe forms of preeclampsia (p = 0.014), in terms of systolic hypertension (p = 0.01) and proteinuria (p = 0.006). According to Spearman correlation analysis, the normalized intensity of SERPINA1 urinary peptides has a similar diagnostic pattern with known diagnostic PE markers, such as sFLT/PLGF. SERPINA1 peptides were not urinary excreted in superimposed PE (PE with CAH), which is a milder form of PE. An increase in expression of SERPINA1 in the structural elements of the placenta during preeclampsia reflects a protective mechanism against hypoxia. Increased synthesis of SERPINA1 in the trophoblast leads to protein accumulation in fibrinoid deposits. It may block syncytial knots and placenta villi, decreasing trophoblast invasion. Excretion of PE specific SERPINA1 peptides is associated with syncytiotrophoblast membrane destruction degradation and increased SERPINA1 staining. It confirms that the placenta could be the origin of SERPINA1 peptides in urine. Significant correlation (p < 0.05) of SERPINA1 expression in syncytiotrophoblast membrane and cytoplasm with the main clinical parameters of severe PE proves the role of SERPINA1 in PE pathogenesis. Estimation of SERPINA1 peptides in urine can be used as a diagnostic test of the severity of the condition to determine further treatment, particularly the need for urgent surgical delivery.

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Yasumatsu, Ryuji, Ozden Altiok, Charaf Benarafa, Chie Yasumatsu, Gulbin Bingol-Karakoc, Eileen Remold-O'Donnell, and Sule Cataltepe. "SERPINB1 upregulation is associated with in vivo complex formation with neutrophil elastase and cathepsin G in a baboon model of bronchopulmonary dysplasia." American Journal of Physiology-Lung Cellular and Molecular Physiology 291, no. 4 (October 2006): L619—L627. http://dx.doi.org/10.1152/ajplung.00507.2005.

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Bronchopulmonary dysplasia (BPD) continues to be a major cause of morbidity in premature infants. An imbalance between neutrophil elastase and its inhibitors has been implicated in BPD. Serine protease inhibitor (SERPIN)B1 is an inhibitor of neutrophil proteases, including neutrophil elastase (NE) and cathepsin G (cat G). Recent studies suggest that SERPINB1 could provide protection in the airways by regulating excess protease activity associated with inflammatory lung disorders. In this study, we determined the distribution and ontogeny of SERPINB1 in the baboon lung and characterized the expression of SERPINB1 in baboon models of BPD. SERPINB1 expression was detected in the conducting airway and glandular epithelial cells in addition to neutrophils, macrophages, and mast cells. SERPINB1 mRNA and protein expression increased with advancing gestational age and in the new BPD model. In contrast, SERPINB1 expression levels were decreased in the old BPD model. Furthermore, SERPINB1 was detected as a high-molecular-mass (HMM) complex in lung tissue and bronchoalveolar lavage fluid samples from the BPD group. Analysis of the HMM complex by coimmunoprecipitation showed that these complexes were formed between SERPINB1 and NE or cat G. High-performance liquid chromatography (HPLC) ion trap mass spectrometry verified the presence of SERPINB1 in HMM complexes. Finally, NE activity level was compared between new and old baboon models of BPD and was found to be significantly lower in new BPD. Thus SERPINB1 upregulation in new BPD may be protective by contributing to the regulation of neutrophil proteases NE and cat G.

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Seker, Fidan, Ahmet Cingoz, İlknur Sur-Erdem, Nazli Erguder, Alp Erkent, Fırat Uyulur, Myvizhi Esai Selvan, et al. "Identification of SERPINE1 as a Regulator of Glioblastoma Cell Dispersal with Transcriptome Profiling." Cancers 11, no. 11 (October 25, 2019): 1651. http://dx.doi.org/10.3390/cancers11111651.

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High mortality rates of glioblastoma (GBM) patients are partly attributed to the invasive behavior of tumor cells that exhibit extensive infiltration into adjacent brain tissue, leading to rapid, inevitable, and therapy-resistant recurrence. In this study, we analyzed transcriptome of motile (dispersive) and non-motile (core) GBM cells using an in vitro spheroid dispersal model and identified SERPINE1 as a modulator of GBM cell dispersal. Genetic or pharmacological inhibition of SERPINE1 reduced spheroid dispersal and cell adhesion by regulating cell-substrate adhesion. We examined TGFβ as a potential upstream regulator of SERPINE1 expression. We also assessed the significance of SERPINE1 in GBM growth and invasion using TCGA glioma datasets and a patient-derived orthotopic GBM model. SERPINE1 expression was associated with poor prognosis and mesenchymal GBM in patients. SERPINE1 knock-down in primary GBM cells suppressed tumor growth and invasiveness in the brain. Together, our results indicate that SERPINE1 is a key player in GBM dispersal and provide insights for future anti-invasive therapy design.

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Li, Qian, Chunmei Li, Jing Jin, Yang Shen, and Mei Wang. "Clinical Significance of Neuregulin 4, Afamin, and SERPINB1 in Gestational Diabetes Mellitus and Their Relationship with Insulin Resistance." Evidence-Based Complementary and Alternative Medicine 2022 (August 28, 2022): 1–8. http://dx.doi.org/10.1155/2022/2829662.

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Objective. This study aims to explore the serum levels of neuregulin 4 (NRG4), afamin (AFM), and serpin family B member 1 (SERPINB1) in gestational diabetes mellitus (GDM) patients and their relationship with insulin resistance. Method. Serum levels of AFM, SERPINB1, and NRG4 were measured in GDM (n = 58), and non-GDM women (n = 60) using enzyme-linked immunosorbent assay (ELISA) kits. Besides, the serum insulin and glucose levels were also measured followed by calculating the homeostatic model assessment of insulin resistance (HOMA-IR). The correlation was performed using the Pearson analysis. Results. The increased serum levels of AFM and SERPINB1 were revealed in GDM patients as compared with non-GDM women, accompanied by the lower NRG4 serum level. ROCs for AFM concentrations showed an AUC of 0.629 (95% CI: 0.527∼0.731), 0.832 (95% CI: 0.754∼0.909) for the SERPINB1 serum level, and 0.626 (95% CI: 0.524∼0.728) for the NRG4 serum level. The threshold was 108.05 mg/L, 8.75 ng/mL, and 96.25 ng/mL of AFM, SERPINB1, and NRG4. Moreover, the combined ROC of AFM, SERPINB1, and NRG4 serum levels showed higher sensitivity (72.41%) and specificity (85.00%) for the diagnosis of GDM (AUC = 0.839; 95% CI: 0.764∼0.913). In GDM patients, the Pearson analysis revealed a significant correlation between AFM and SERPINB1 (r = 0.776), AFM and NRG4 (r = −0.799), as well as SERPINB1 and NRG4 (r = −0.783). Moreover, AFM and SERPINB1 serum concentrations in GDM patients were positively related to insulin levels, fasting glucose levels, and HOMA-IR values. However, the SERPINB1 serum level was negatively correlated with serum insulin and glucose levels and HOMA-IR. Conclusion. Abnormal serum levels of NRG4, AFM, and SERPINB1, as highly sensitive diagnostic tools, are closely related to insulin resistance in GDM patients.

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Fraquelli, Cristina, Jasmine Hauzinger, Christian Humpel, Maria Nolano, Vincenzo Provitera, Vinay Kumar Sharma, Peng Loh, Zenon Pidsudko, Georgios Blatsios, and Josef Troger. "Serpinin in the Skin." Biomedicines 10, no. 1 (January 16, 2022): 183. http://dx.doi.org/10.3390/biomedicines10010183.

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The serpinins are relatively novel peptides generated by proteolytic processing of chromogranin A and they are comprised of free serpinin, serpinin-RRG and pGlu-serpinin. In this study, the presence and source of these peptides were studied in the skin. By Western blot analysis, a 40 kDa and a 50 kDa protein containing the sequence of serpinin were detected in the trigeminal ganglion and dorsal root ganglia in rats but none in the skin. RP-HPLC followed by EIA revealed that the three serpinins are present in similar, moderate amounts in rat dorsal root ganglia, whereas in the rat skin, free serpinin represents the predominant molecular form. There were abundant serpinin-positive cells in rat dorsal root ganglia and colocalization with substance P was evident. However, much more widespread distribution of the serpinins was found in dorsal root ganglia when compared with substance P. In the skin, serpinin immunoreactivity was found in sensory nerves and showed colocalization with substance P; as well, some was present in autonomic nerves. Thus, although not exclusively, there is evidence that serpinin is a constituent of the sensory innervation of the skin. The serpinins are biologically highly active and might therefore be of functional significance in the skin.

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Journal articles on the topic 'SERPINI1'

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