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Proteinase Inhibitors: An Overview of their Structure and Possible Function in the Acute Phase
Published in Andrzej Mackiewicz, Irving Kushner, Heinz Baumann, Acute Phase Proteins, 2020
Rats contain two PSTI genes, one of which (PSTI-1) is expressed mainly in the pancreas and the other of which is expressed in pancreas and liver (PSTI-2).57 The two genes are very closely related in primary sequence, indicating that they diverged during rodent speciation. Only one ortholog is found in cows and humans. The role of PSTI is thought to be the prevention of adventitious proteolysis in the pancreas due to premature activation of trypsin, although the expression of human PSTI and rat PSTI-2 in liver raises the possibility of an extrapancreatic role.
Role of Engineered Proteins as Therapeutic Formulations
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Khushboo Gulati, Krishna Mohan Poluri
Kunitz domain is found in numerous proteases, including bovine pancreatic trypsin inhibitor (BPTI), human pancreatic secretory trypsin inhibitor (PSTI), and ecotin (periplasmic E. coli protease inhibitor). Kunitz domains are also involved as ion channel blockers as they mainly inhibit serine proteases. Structurally, kunitz domains are 60 amino acids long that are arranged in form of a mixture of α-helices and β-sheets. The core structure of the Kunitz domain is stabilized by three disulfide bonds that also make the structure compact and protect it from proteases (Ranasinghe and McManus, 2013). Lehmann et al. engineered small protein known as Ecallantide (DX-88) based on Kunitz domain using phage display technology. It acts as an inhibitor of plasma kallikrein that plays a major role in contact cascade to produce bradykinin (Lehmann, 2008). Dennis et al. designed Kunitz domain variants from Alzheimer’s amyloid beta-protein precursor inhibitor (APPI), to inhibit the association of human tissue factor-Factor VIIa complex (TF.FVIIa) (Dennis and Lazarus, 1994).
Common Inherited Genetic Disorders
Published in Attila Lorincz, Nucleic Acid Testing for Human Disease, 2016
A very rare polymorphism has been described in the 3′ primer used in some assays. This polymorphism can potentially disrupt primer binding to an HD chromosome and result in a false negative result. Apparent normal homozygous results should be evaluated for the presence of a polymorphism that results in failure to amplify one allele. This is a common pitfall for all PCR-based analyses. The use of alternative primers often allows resolution of two normal alleles in cases having identical numbers of CAG repeats but different numbers of CCG repeats.52 Alternatively, a Southern blot using PstI-digested DNA hybridized to the 4G6P1.7 probe allows evaluation for large expansions and alleles that fail to amplify by PCR.
Tumor-associated trypsin inhibitor (TATI) and tumor-associated trypsin-2 (TAT-2) predict outcomes in gastric cancer
Published in Acta Oncologica, 2020
Aaro Kasurinen, Alli Laitinen, Arto Kokkola, Ulf-Håkan Stenman, Camilla Böckelman, Caj Haglund
Tumor-associated trypsin inhibitor (TATI), also known as the pancreatic secretory trypsin inhibitor (PSTI), is a serine protease inhibitor first found in the urine of a patient with gynecological cancer [3,4], called serine peptidase inhibitor Kazal-type 1 (SPINK1). In addition to inhibiting serine proteases, it appears to promote carcinogenesis by activating the epidermal growth factor receptors (EGFRs) [5,6]. In addition to gastric cancer, TATI expresses in several other cancers, including colorectal, pancreatic, ovarian, bladder, renal, prostate, lung, breast and liver cancers, and appears useful for both diagnostic and prognostic purposes [6]. The prognostic role of TATI in gastric cancer remains controversial since, on the one hand, a high TATI expression in gastric carcinoma tissues served as a marker of a favorable outcome and associated with a low cancer stage, superficial tumors and the absence of metastasis. On the other hand, higher serum TATI levels were found more often among gastric cancer patients than among controls and associated with advanced disease [7,8]. Additionally, TATI acts as an acute-phase reactant and the regulation of its synthesis resembles that of the C-reactive protein (CRP) and other acute-phase reactants [9,10]. Thus, in addition to malignant diseases, an elevated serum TATI level may result from an inflammation caused by an infection or tissue damage [11,12].
Possible association between DNA repair gene variants and cannabis dependence in a Turkish cohort: a pilot study
Published in Psychiatry and Clinical Psychopharmacology, 2018
Sacide Pehlivan, Ahmet Bulent Yazici, Nazan Aydin, Ayse Feyda Nursal, Selin Kurnaz, Ayca Ongel Atar, Ulgen Sever, Zeliha Kincir, Mustafa Pehlivan, Pınar Cetinay Aydin
A 5-ml venous blood sample was collected in EDTA vacuum tubes. Genomic DNA was extracted from each blood sample using the salting out procedure [9]. Genotyping was performed by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method previously described [10]. PCR was performed in a final volume of 25 μl containing 65 mM tris-HCl (pH 8.9), 24 mM (NH4)2SO4, 3 mM MgCl2, 0.05% Twin-20, 0.2 mM deoxynucleoside triphosphate solution, 0.3 μM solution of oligonucleotide primers [XRCC1 Arg399Gln (rs25487): F5′-AGT AGT CTG CTG GCT CTG G-3′, R5′-TCT CCC TTG GTC TCC AAC CT-3′; XRCC4 G1394 T (rs6869366): F5′-GAT GCG AAC TCA AAG ATA CTG A-3′, R5′-TGT AAA GCC AGT ACT CAA ACT T-3′; 13181:F5′-ATC CTG TCC CTA CTG GCC ATT C-3′, R5′-TGT GGA CGT GAC AGT GAG AAA T-3′; XPD (rs13181): F5′-ATC CTG TCC CTA CTG GCC ATT C-3′, R5′-TGT GGA CGT GAC AGT GAG AAA T-3′), 20–100 ng DNA, and 2 U TaqDNA polymerase. PCR was performed using ABI-9600 with initial denaturation at 96°C for 3 min, then 32 cycles at 55°C for rs25487 and rs25487; 60°C for rs13181 and then last cycle at 72°C for 8 min. Genotyping for XRCC1 (rs25487), XRCC4 (rs6869366), and XPD (rs13181) variants involved digestion of PCR products with MspI, HincII, and PstI restriction endonucleases, respectively, at 37°C for overnight incubation. All of the digestion products were visualized by electrophoresis on a 2% agarose gel. The experimental process was repeated twice for each sample.
Unique properties of IgG4 antibody and its clinical application in autoimmune pancreatitis
Published in Scandinavian Journal of Gastroenterology, 2018
Presently, much attention has been paid to organ-specific autoantibodies because of their potential pathogenic relevance to the initiation of the disease. Several disease-specific autoantibodies aiming at pancreas-specific autoantigens such as LF [97], CA-II\IV [97–101], heat-shock protein (HSP)-10 [102], pancreatic trypsinogens [103], pancreatic secretory trypsin inhibitor (PSTI) [104], Annexin A11 [35] have been reported. Autoantibodies to amylase alpha 2A [105] and plasminogen-binding protein (PBP) [80] seem to have a high sensitivity and specificity in AIP. Generally, these antibodies are not entirely specific for AIP, and can be detected in other autoimmune diseases [101,106]. Although studies concerning the role of IgG4 as a direct, pathogenic antibody have been reported elsewhere [107–110], the major subclass of these autoantibodies for AIP is not necessarily IgG4. On the contrary, antibody against PSTI and Annexin A11 are often IgG1 and that IgG4 may be upregulated as an anti-inflammatory measure that blocks pathogenic IgG1 [35,104]. So far, there is no convincing study to clarify or confirm the subclasses of these reported autoantibodies.