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Frontiers in Cardiovascular Medicine 2020Alpha2-antiplasmin (α2AP), the fast-reacting, serine protease inhibitor (serpin) of plasmin, was originally thought to play a key role in protection against...
Alpha2-antiplasmin (α2AP), the fast-reacting, serine protease inhibitor (serpin) of plasmin, was originally thought to play a key role in protection against uncontrolled, plasmin-mediated proteolysis of coagulation factors and other molecules. However, studies of humans and mice with genetic deficiency of α2AP have expanded our understanding of this serpin, particularly in disease states. Epidemiology studies have shown an association between high α2AP levels and increased risk or poor outcome in cardiovascular diseases. Mechanistic studies in disease models indicate that α2AP stops the body's own fibrinolytic system from dissolving pathologic thrombi that cause venous thrombosis, pulmonary embolism, arterial thrombosis, and ischemic stroke. In addition, α2AP fosters the development of microvascular thrombosis and enhances matrix metalloproteinase-9 expression. Through these mechanisms and others, α2AP contributes to brain injury, hemorrhage and swelling in experimental ischemic stroke. Recent studies also show that α2AP is required for the development of stasis thrombosis by inhibiting the early activation of effective fibrinolysis. In this review, we will discuss the key role played by α2AP in controlling thrombosis and fibrinolysis and, we will consider its potential value as a therapeutic target in cardiovascular diseases and ischemic stroke.
PubMed: 33426005
DOI: 10.3389/fcvm.2020.608899 -
Prostate Cancer and Prostatic Diseases Sep 2020The androgen receptor (AR) is a key prostate cancer drug target. Suppression of AR signaling mediated by the full-length AR (AR-FL) is the therapeutic goal of all...
BACKGROUND
The androgen receptor (AR) is a key prostate cancer drug target. Suppression of AR signaling mediated by the full-length AR (AR-FL) is the therapeutic goal of all existing AR-directed therapies. AR-targeting agents impart therapeutic benefit, but lead to AR aberrations that underlie disease progression and therapeutic resistance. Among the AR aberrations specific to castration-resistant prostate cancer (CRPC), AR variants (AR-Vs) have emerged as important indicators of disease progression and therapeutic resistance.
METHODS
We conducted a systemic review of the literature focusing on recent laboratory studies on AR-Vs following our last review article published in 2016. Topics ranged from measurement and detection, molecular origin, regulation, genomic function, and preclinical therapeutic targeting of AR-Vs. We provide expert opinions and perspectives on these topics.
RESULTS
Transcript sequences for 22 AR-Vs have been reported in the literature. Different AR-Vs may arise through different mechanisms, and can be regulated by splicing factors and dictated by genomic rearrangements, but a low-androgen environment is a prerequisite for generation of AR-Vs. The unique transcript structures allowed development of in situ and in-solution measurement and detection methods, including mRNA and protein detection, in both tissue and blood specimens. AR-V7 remains the main measurement target and the most extensively characterized AR-V. Although AR-V7 coexists with AR-FL, genomic functions mediated by AR-V7 do not require the presence of AR-FL. The distinct cistromes and transcriptional programs directed by AR-V7 and their coregulators are consistent with genomic features of progressive disease in a low-androgen environment. Preclinical development of AR-V-directed agents currently focuses on suppression of mRNA expression and protein degradation as well as targeting of the amino-terminal domain.
CONCLUSIONS
Current literature continues to support AR-Vs as biomarkers and therapeutic targets in prostate cancer. Laboratory investigations reveal both challenges and opportunities in targeting AR-Vs to overcome resistance to current AR-directed therapies.
Topics: Alternative Splicing; Androgen Receptor Antagonists; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Clinical Decision-Making; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Genetic Testing; Humans; Male; Precision Medicine; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Protein Isoforms; Proteolysis; Receptors, Androgen; Transcriptional Activation
PubMed: 32139878
DOI: 10.1038/s41391-020-0217-3 -
Chinese Journal of Traumatology =... Apr 2019The clinical treatment of joint contracture due to immobilization remains difficult. The pathological changes of muscle tissue caused by immobilization-induced joint...
The clinical treatment of joint contracture due to immobilization remains difficult. The pathological changes of muscle tissue caused by immobilization-induced joint contracture include disuse skeletal muscle atrophy and skeletal muscle tissue fibrosis. The proteolytic pathways involved in disuse muscle atrophy include the ubiquitin-proteasome-dependent pathway, caspase system pathway, matrix metalloproteinase pathway, Ca-dependent pathway and autophagy-lysosomal pathway. The important biological processes involved in skeletal muscle fibrosis include intermuscular connective tissue thickening caused by transforming growth factor-β1 and an anaerobic environment within the skeletal muscle leading to the induction of hypoxia-inducible factor-1α. This article reviews the progress made in understanding the pathological processes involved in immobilization-induced muscle contracture and the currently available treatments. Understanding the mechanisms involved in immobilization-induced contracture of muscle tissue should facilitate the development of more effective treatment measures for the different mechanisms in the future.
Topics: Atrophy; Autophagy; Calcium; Caspases; Connective Tissue; Contracture; Fibrosis; Humans; Immobilization; Joints; Lysosomes; Matrix Metalloproteinases; Muscle, Skeletal; Proteasome Endopeptidase Complex; Proteolysis; Signal Transduction; Transforming Growth Factor beta1; Ubiquitin
PubMed: 30928194
DOI: 10.1016/j.cjtee.2019.02.001 -
Clinical Gastroenterology and... Aug 2018Tests to quantify fecal levels of chymotrypsin like elastase family member 3 (CELA3 or elastase-1) in feces are widely used to identify patients with exocrine pancreatic... (Meta-Analysis)
Meta-Analysis
BACKGROUND & AIMS
Tests to quantify fecal levels of chymotrypsin like elastase family member 3 (CELA3 or elastase-1) in feces are widely used to identify patients with exocrine pancreatic insufficiency (EPI). However, the diagnostic accuracy of this test, an ELISA, is not clear. We performed a systematic review and meta-analysis to determine the accuracy of measurement of fecal elastase-1 in detection of EPI.
METHODS
We searched PubMed, Embase, and reference lists for articles through November 2016 describing studies that compared fecal level of elastase-1 with results from a reference standard, direct method (secretin stimulation test), or indirect method (measurement of fecal fat) for detection of EPI. Sensitivity and specificity values were pooled statistically using bivariate diagnostic meta-analysis.
RESULTS
We included total of 428 cases of EPI and 673 individuals without EPI (controls), from 14 studies, in the meta-analysis. The assay for elastase-1, compared to secretin stimulation test, identified patients with pancreatic insufficiency with a pooled sensitivity value of 0.77 (95% CI, 0.58-0.89) and specificity value of 0.88 (95% CI, 0.78-0.93). In an analysis of 345 cases of EPI and 312 controls, from 6 studies, the fecal elastase-1 assay identified patients with EPI with a pooled sensitivity value of 0.96 (95% CI, 0.79-0.99) and specificity value of 0.88 (95% CI, 0.59-0.97), compared to quantitative fecal fat estimation. In patients with low pre-test probability of EPI (5%), the fecal elastase-1 assay would have a false-negative rate of 1.1% and a false-positive rate of 11%, indicating a high yield in ruling out EPI but not in detection of EPI. In contrast, in patients with high pre-test probability of EPI (40%), approximately 10% of patients with EPI would be missed (false negatives).
CONCLUSIONS
In a systematic review and meta-analysis of studies that compared fecal level of elastase-1 for detection of EPI, we found that normal level of elastase-1 (above 200 mcg/g) can rule out EPI in patients with a low probability of this disorder (such as those with irritable bowel syndrome with diarrhea). However, in these patients, an abnormal level of elastase-1 (below 200 mcg/g) has a high false-positive rate.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Child, Preschool; Diagnostic Tests, Routine; Exocrine Pancreatic Insufficiency; Feces; Female; Humans; Infant; Infant, Newborn; Male; Middle Aged; Pancreatic Elastase; Sensitivity and Specificity; Young Adult
PubMed: 29374614
DOI: 10.1016/j.cgh.2018.01.027 -
Brazilian Journal of Microbiology :... 2017Specific proteases capable of degrading native triple helical or denatured collagen have been required for many years and have a large spectrum of applications. There... (Meta-Analysis)
Meta-Analysis Review
Specific proteases capable of degrading native triple helical or denatured collagen have been required for many years and have a large spectrum of applications. There are few complete reports that fully uncover production, characterization and purification of fungi collagenases. In this review, authors searched through four scientific on line data bases using the following keywords (collagenolytic OR collagenase) AND (fungi OR fungus OR fungal) AND (production OR synthesis OR synthesize) AND (characterization). Scientific criteria were adopted in this review to classify found articles by score (from 0 to 10). After exclusion criteria, 21 articles were selected. None obtained the maximum of 10 points defined by the methodology, which indicates a deficiency in studies dealing simultaneously with production, characterization and purification of collagenase by fungi. Among microorganisms studied the non-pathogenic fungi Penicillium aurantiogriseum and Rhizoctonia solani stood out in volumetric and specific collagenase activity. The only article found that made sequencing of a true collagenase showed 100% homology with several metalloproteinases fungi. A clear gap in literature about collagenase production by fungi was verified, which prevents further development in the area and increases the need for further studies, particularly full characterization of fungal collagenases with high specificity to collagen.
Topics: Collagen; Collagenases; Culture Media; Enzyme Activation; Fungi; Proteolysis; Substrate Specificity
PubMed: 27756540
DOI: 10.1016/j.bjm.2016.08.001