Inherited Differences in Alpha1-Antitrypsin
Stephen D. Litwin in Genetic Determinants of Pulmonary Disease, 2020
Antiproteolytic activity in mammalian sera is not a new observation; it was first observed by investigators during the last century [4,5]. Advances in protein chemistry have revealed that this activity is due to a group of individual inhibitors. Human serum alone contains seven distinct major protease inhibitors (Table 1) which differ in their specificity range. For example, alpha2macroglobulin shows a broad spectrum of inhibition which includes proteases with different mechanisms of action such as trypsin and papain [6]. Alpha1antichymotrypsin neutralizes only chymotrypsin and chymotrypsin-like enzymes; it does not inhibit trypsin. The recently described anti-collagenase is apparently quite specific [7]. Other enzymes have not been extensively tested. The major inhibitors present in human sera are listed in Table 1.
Interleukin-6 and the Lung
Jason Kelley in Cytokines of the Lung, 2022
Interleukin-6 has complicated effects on hepatic acute-phase proteins. Typically, IL-6 increases hepatic acute-phase protein production; however, several “negative acute-phase reactants,” such as albumin and alpha1-inhibitor III have been described, the synthesis of which is decreased in response to IL-6 (Baumann et al., 1987; Abraham et al., 1990). The proteins induced by IL-6 have been divided into two categories (Baumann and Gauldie, 1990). Group 1 proteins are produced by hepatocytes in response to IL-6 alone. Group 2 proteins are maximally produced only when hepatocytes are stimulated with IL-1 and IL-6 simultaneously. Group 1 includes hemopexin, complement factor III, haptoglobin, and alpha1-acid glycoprotein. Group 2 proteins include alpha1-antitrypsin, alpha1-antichymotrypsin, thiostatin, fibrinogen, and alpha2-macroglobulin. The complexity of the regulation is illustrated by the fact that IL-1 augments IL-6–induced production of group 2 proteins, while diminishing IL-6–induced production of group 1 proteins. In addition, glucocorticoids may interact with IL-1 and IL-6 in a permissive or synergistic manner to induce acute-phase protein synthesis by directly modulating acute-phase protein gene transcription and altering cell surface cytokine receptors (Sehgal, 1990).
Treatment Of Alzheimer’s Disease
Zaven S. Khachaturian, Teresa S. Radebaugh in Alzheimer’s Disease, 2019
There is evidence from histological studies that the immune system plays a role in AD. Increased numbers of reactive glia and microglia as well as activated T lymphocytes have been observed in post-mortem brain tissue (Haga et al., 1989; Rogers et al., 1988). Complement proteins including the membrane attack proteins C5-C9 have also been identified in senile plaques, tangles, and dystrophic neurites (Eikelenboom et al., 1989; McGeer et al., 1992). It seems that the process involves the complement cascade through the activation of clq by AB (Eikelenboom et al., 1989; Rogers et al., 1992; Rogers et al., 1992). Elevated concentrations of tumor necrosis factor, Inter-leukin 1(11-1) and interleukin 6 (11-6) have also been demonstrated (Fillit et al., 1991; Bauer et al., 1991). Since interleukins can enhance APP production, their presence in the AD brain may be important (Alstiel and Sperber, 1991). Acute phase reactants are also elevated in AD, and alpha 2 macroglobulin and alpha 1 antichymotrypsin (ACT) have been demonstrated in amyloid deposits in AD (Abraham et al., 1988; Rozemuller et al., 1990; Bauer et al., 1991).
Mass spectrometry analysis of glycoprotein biomarkers in human blood of hepatocellular carcinoma
Published in Expert Review of Proteomics, 2019
Kwang Hoe Kim, Jin Young Kim, Jong Shin Yoo
Abnormally glycosylated serum proteins are potential biomarkers of HCC. Glycosylation is one of the most common PTMs, and is associated with intercellular adhesion, protein–ligand interactions, and cell differentiation [36]. A number of glycosylated proteins are reportedly biomarkers of HCC. Haptoglobin (Hp) is secreted and degraded mainly in the liver. Hp is a glycoprotein consisting of α1, α2, and β chains, and plays a critical role in malignancy and inflammation [37]. The β chain of Hp contains four N-glycosylation sites, which can be sialylated, highly branched, and fucosylated in patients with cancer [38–41]. The level of fucosylation of Hp was upregulated in patients with HCC [42–45]. Alpha-1-acid glycoprotein (AGP) is normally synthesized in the liver [46] and, as an acute-phase protein, is closely associated with inflammation. The serum level of AGP has promise as a biomarker for HCC [47] and was able to discriminate patients with HCC and those with other liver diseases who had a low serum AFP level [48]. In addition, altered sialylation or fucosylation of serum AGP is increased in serum of patients with HCC and cirrhosis [49]. Alpha-1-antichymotrypsin (AACT) is a liver-derived serum glycoprotein with protease inhibitory activity [50]. AACT is an acute-phase protein associated with inflammation and tissue injury [51]. AACT is upregulated in patients with moderately differentiated HCC versus those with well or poorly differentiated HCC [52]. Also, tri-antennary glycoforms of AACT have potential as biomarkers of HCC [53].
Digital rectal examination in prostate cancer screening at PSA level 3.0-3.9 ng/ml: long-term results from a randomized trial
Published in Scandinavian Journal of Urology, 2021
Veera Soronen, Kirsi Talala, Jani Raitanen, Kimmo Taari, Teuvo Tammela, Anssi Auvinen
Earlier studies have recognized free/total PSA ratio to be lower among men with PC [26,27]. This was discovered in the 1990s when it became apparent that the proportion of the PSA-alpha 1-antichymotrypsin complex was higher in patients with PC than in those with benign hyperplasia [28]. Using free/total PSA ratio improved the efficiency of PSA by eliminating half of the false-positive results without loss of sensitivity in a Finnish study [29]. This was supported by another study which found that using a positive free/total PSA result as a biopsy criterion 30% of the negative biopsies could be eliminated, while still detecting 98% of the cancers [27]. The study used a 0.22 cutoff point for free/total PSA, which was slightly higher than that of ours (0.16). Despite this, our results were similar and regarded free/total PSA ratio as a statistically significant predictor of PC.
Prostate cancer biomarkers: a practical review based on different clinical scenarios
Published in Critical Reviews in Clinical Laboratory Sciences, 2022
Ugo Giovanni Falagario, Francesca Sanguedolce, Zach Dovey, Umberto Carbonara, Fabio Crocerossa, George Papastefanou, Riccardo Autorino, Marco Recchia, Antonella Ninivaggi, Gian Maria Busetto, Pasquale Annese, Giuseppe Carrieri, Luigi Cormio
PSA is a serine protease whose function is to keep semen fluid after ejaculation, allowing sperm to move more easily through the cervix. It is part of the kallikrein family, a group of 15 serine proteases known for their role in regulating cell growth, remodeling and degrading the extracellular matrix, and promoting cell invasion and angiogenesis [14]. Human kallikrein-3, also known as PSA, and human kallikrein-2 (hK2) are the dominant forms and allow the contents of the vas deferens to be maintained as a liquid. They exist as proproteins, pro-PSA (p2PSA) and pro-hK2, and are split to generate active enzymic forms. Circulating levels of both kallikreins increase as the tumor becomes more poorly differentiated, perhaps due to loss of tissue architecture [15]. Furthermore, once in circulation, they are rapidly bound by antichymotrypsin (ACT) or inhibited by proteolysis. About 30% of PSA is present in the serum in a free form, whereas 70% is in a form bound to protease inhibitors, alpha-1-antichymotrypsin and alpha-2-macroglobulin.