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Journal of Digestive Diseases Oct 2014Methotrexate is effective not only in treating psoriasis and rheumatoid arthritis but also various other disorders. The use of methotrexate has been somewhat limited by... (Review)
Review
Methotrexate is effective not only in treating psoriasis and rheumatoid arthritis but also various other disorders. The use of methotrexate has been somewhat limited by concerns regarding its adverse effects, including its potential for hepatotoxicity. The purpose of this article is to provide an overview of methotrexate-associated hepatotoxicity, including risk factors, pathogenesis and recommendations for monitoring it by US, UK and European guidelines, as well as providing a brief overview of its mechanism of action and of high-dose methotrexate.
Topics: Antimetabolites, Antineoplastic; Antirheumatic Agents; Biomarkers; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drug Monitoring; Folic Acid; Humans; Methotrexate; Peptide Fragments; Procollagen; Risk Factors
PubMed: 25139707
DOI: 10.1111/1751-2980.12184 -
Life Science Alliance May 2022The processing of type I procollagen is essential for fibril formation; however, the steps involved remain controversial. We constructed a live cell imaging system by...
The processing of type I procollagen is essential for fibril formation; however, the steps involved remain controversial. We constructed a live cell imaging system by inserting fluorescent proteins into type I pre-procollagen α1. Based on live imaging and immunostaining, the C-propeptide is intracellularly cleaved at the perinuclear region, including the endoplasmic reticulum, and subsequently accumulates at the upside of the cell. The N-propeptide is also intracellularly cleaved, but is transported with the repeating structure domain of collagen into the extracellular region. This system makes it possible to detect relative increases and decreases in collagen secretion in a high-throughput manner by assaying fluorescence in the culture medium, and revealed that the rate-limiting step for collagen secretion occurs after the synthesis of procollagen. In the present study, we identified a defect in procollagen processing in activated hepatic stellate cells, which secrete aberrant collagen fibrils. The results obtained demonstrated the intracellular processing of type I procollagen, and revealed a link between dysfunctional processing and diseases such as hepatic fibrosis.
Topics: Collagen; Endoplasmic Reticulum; Procollagen
PubMed: 35181633
DOI: 10.26508/lsa.202101060 -
PloS One 2019The balance between bone resorption and formation may be assessed by measurement of bone turnover markers (BTMs), like carboxyl-terminal cross-linked telopeptide of type...
The balance between bone resorption and formation may be assessed by measurement of bone turnover markers (BTMs), like carboxyl-terminal cross-linked telopeptide of type 1 collagen (CTX-1) and procollagen type 1 amino-terminal propeptide (P1NP). Smoking has been shown to influence bone turnover and to reduce bone mass density (BMD), the exact mechanism for this is, however, not settled. In this post-hoc study including 406 subjects (mean age 51.9 years), we aimed to study the impact of smoking on bone turnover. Moreover, we wanted to assess the inter-correlation between substances regulating bone metabolism and BTMs, as well as tracking over time. BMD measurements and serum analyses of CTX-1, P1NP, osteoprotegerin (OPG), receptor activator of nuclear factor ĸB ligand (RANKL), Dickkopf-1 (DKK1), sclerostin, tumor necrosis factor-α (TNF-α), and leptin were performed. Repeated serum measurements were made in 195 subjects after four months. Adjustments were made for sex, age, body mass index (BMI), smoking status, insulin resistance, serum calcium, parathyroid hormone, 25-hydroxyvitamin D and creatinine. Smokers had higher levels of DKK1 and OPG, and lower levels of RANKL, as reflected in lower BTMs and BMD compared to non-smokers. There were strong and predominantly positive inter-correlations between BTMs and the other substances, and there was a high degree of tracking with Spearman's rho from 0.72 to 0.92 (P < 0.001) between measurements four months apart. In conclusion, smokers exhibited higher levels of DKK1 and OPG and a lower bone turnover than did non-smokers. The strong inter-correlations between the serum parameters illustrate the coupling between bone resorption and formation and crosstalk between cells.
Topics: Adult; Biomarkers; Bone Density; Bone Remodeling; Female; Humans; Intercellular Signaling Peptides and Proteins; Male; Middle Aged; Osteoprotegerin; Parathyroid Hormone; Peptide Fragments; Procollagen; RANK Ligand; Smoking; Vitamin D
PubMed: 31765401
DOI: 10.1371/journal.pone.0225539 -
Hepatology Communications Mar 2022Hepatic fibrosis is driven by deposition of matrix proteins following liver injury. Hepatic stellate cells (HSCs) drive fibrogenesis, producing matrix proteins,...
Hepatic fibrosis is driven by deposition of matrix proteins following liver injury. Hepatic stellate cells (HSCs) drive fibrogenesis, producing matrix proteins, including procollagen I, which matures into collagen I following secretion. Disrupting intracellular procollagen processing and trafficking causes endoplasmic reticulum stress and stress-induced HSC apoptosis and thus is an attractive antifibrotic strategy. We designed an immunofluorescence-based small interfering RNA (siRNA) screen to identify procollagen I trafficking regulators, hypothesizing that these proteins could serve as antifibrotic targets. A targeted siRNA screen was performed using immunofluorescence to detect changes in intracellular procollagen I. Tumor necrosis factor receptor associated factor 2 and noncatalytic region of tyrosine kinase-interacting kinase (TNIK) was identified and interrogated in vitro and in vivo using the TNIK kinase inhibitor NCB-0846 or RNA interference-mediated knockdown. Our siRNA screen identified nine genes whose knockdown promoted procollagen I retention, including the serine/threonine kinase TNIK. Genetic deletion or pharmacologic inhibition of TNIK through the small molecule inhibitor NCB-0846 disrupted procollagen I trafficking and secretion without impacting procollagen I expression. To investigate the role of TNIK in liver fibrogenesis, we analyzed human and murine livers, finding elevated TNIK expression in human cirrhotic livers and increased TNIK expression and kinase activity in both fibrotic mouse livers and activated primary human HSCs. Finally, we tested whether inhibition of TNIK kinase activity could limit fibrogenesis in vivo. Mice receiving NCB-0846 displayed reduced CCl -induced fibrogenesis compared to CCl alone, although α-smooth muscle actin levels were unaltered. Conclusions: Our siRNA screen effectively identified TNIK as a key kinase involved in procollagen I trafficking in vitro and hepatic fibrogenesis in vivo.
Topics: Animals; Liver; Mice; Procollagen; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; RNA, Small Interfering; TNF Receptor-Associated Factor 2
PubMed: 34677004
DOI: 10.1002/hep4.1835 -
Current Cardiology Reports May 2020Biomarkers of cardiac fibrosis closely track the disease state that gives rise to heart failure. The purpose of this review is to highlight recent data on the use of... (Review)
Review
PURPOSE OF REVIEW
Biomarkers of cardiac fibrosis closely track the disease state that gives rise to heart failure. The purpose of this review is to highlight recent data on the use of soluble ST2, galectin-3, and procollagen, three markers of cardiac fibrosis, for aiding with prognostication, and to explore the use of these biomarkers for guiding therapy.
RECENT FINDINGS
Soluble ST2, galectin-3, and procollagen are prognostic in both acute and chronic heart failure, and data are emerging as to their potential uses for guiding therapies. Mortality benefit from exercise, cardiac resynchronization therapy, statin use, as well as anti-fibrotic therapies such as aldosterone antagonism may vary based upon levels of these fibrosis markers. Soluble ST2, galectin-3, and procollagen provide independent prognostic information for heart failure morbidity and mortality. Markers of cardiac fibrosis may also help identify the subsets of patients who are most likely to benefit from various therapies. However, further studies are needed prior to formalizing individual patient care algorithms guided by fibrosis biomarkers.
Topics: Biomarkers; Fibrosis; Galectin 3; Heart Failure; Humans; Interleukin-1 Receptor-Like 1 Protein; Predictive Value of Tests; Procollagen; Prognosis
PubMed: 32430626
DOI: 10.1007/s11886-020-01288-z -
World Journal of Pediatrics : WJP Nov 2015Most congenital heart diseases (CHDs) have specific hemodynamics, including volume and pressure overload, as well as cyanosis and pulmonary hypertension, associated with... (Review)
Review
BACKGROUND
Most congenital heart diseases (CHDs) have specific hemodynamics, including volume and pressure overload, as well as cyanosis and pulmonary hypertension, associated with anatomical abnormalities. Such hemodynamic abnormalities can cause activation of neurohormones, inflammatory cytokines, fibroblasts, and vascular endothelial cells, which in turn contribute to the development of pathologic conditions such as cardiac hypertrophy, fibrosis, and cardiac cell damages and death. Measuring biomarker levels facilitates the prediction of these pathological changes, and provides information about the stress placed on the myocardial cells, the severity of the damage, the responses of neurohumoral factors, and the remodeling of the ventricle. Compared to the ample information on cardiac biomarkers in adult heart diseases, data from children with CHD are still limited.
DATA SOURCES
We reviewed cardiac biomarkers-specifically focusing on troponin as a biomarker of myocardial damage, amino-terminal procollagen type III peptide (PIIIP) as a biomarker of myocardial fibrosis and stromal remodeling, and B-type natriuretic peptide (BNP)/N-terminal proBNP as biomarkers of cardiac load and heart failure, by introducing relevant publications, including our own, on pediatric CHD patients as well as adults.
RESULTS
Levels of highly sensitive troponin I are elevated in patients with atrial septal defects (ASDs) and ventricular septal defects (VSDs). PIIIP levels are also elevated in patients with ASD, VSD, pulmonary stenosis, and Tetralogy of Fallot. Measurement of BNP and N-terminal proBNP levels shows good correlation with heart failure score in children.
CONCLUSIONS
In the treatment of children with CHD requiring delicate care, it is vital to know the specific degree of myocardial damage and severity of heart failure. Cardiac biomarkers are useful tools for ascertaining the condition of CHDs with ease and are likely to be useful in determining the appropriate care of pediatric cardiology patients.
Topics: Adolescent; Adult; Biomarkers; Child; Child, Preschool; Heart Defects, Congenital; Humans; Infant; Infant, Newborn; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Procollagen; Troponin
PubMed: 26454435
DOI: 10.1007/s12519-015-0039-x -
Current Osteoporosis Reports Jun 2017Impaired bone quality contributes to the increased fracture risk in chronic kidney disease patients. Both low and high turnover bone disease may compromise bone quality.... (Review)
Review
PURPOSE OF THE REVIEW
Impaired bone quality contributes to the increased fracture risk in chronic kidney disease patients. Both low and high turnover bone disease may compromise bone quality. The question arises whether bone biomarkers may be additive or replace bone histormorphometry for diagnosing the extremes of bone turnover.
RECENT FINDINGS
Studies exploring the performance of established and emerging bone biomarkers against histomorphometric assessment of bone turnover are limited and overall yield inconclusive results as to their diagnostic utility. Bone biomarkers, although promising, currently fail to meet the needed diagnostic accuracy to replace bone histomorphometry and thus are not yet ready for clinical use. Bone biomarkers have not only several advantages, but also important limitations such as high biological variability, retention with kidney disease, preanalytical issues, and interassay variability. These important issues must be considered when developing and evaluating bone biomarkers. There is an urgent need for harmonization and standardization of available assays and additional bone biopsy studies.
Topics: Adaptor Proteins, Signal Transducing; Alkaline Phosphatase; Biomarkers; Bone Remodeling; Humans; Intracellular Signaling Peptides and Proteins; Osteocalcin; Parathyroid Hormone; Peptide Fragments; Procollagen; Proteins; Renal Insufficiency, Chronic
PubMed: 28429254
DOI: 10.1007/s11914-017-0362-3 -
Arthritis & Rheumatology (Hoboken, N.J.) Oct 2023Transport and Golgi Organization protein 1 (TANGO1) is a protein that regulates the export of procollagen from the endoplasmic reticulum and has a role in the...
Caspase 1 Enhances Transport and Golgi Organization Protein 1 Expression to Promote Procollagen Export From the Endoplasmic Reticulum in Systemic Sclerosis Contributing to Fibrosis.
OBJECTIVE
Transport and Golgi Organization protein 1 (TANGO1) is a protein that regulates the export of procollagen from the endoplasmic reticulum and has a role in the organization of exit sites for general protein export. What regulates the expression of TANGO1 and the role of TANGO1 in fibrosis is poorly understood and has never been studied in the setting of systemic sclerosis (SSc). We undertook this study to determine the role of TANGO1 in SSc fibrosis.
METHODS
SSc (n = 15) and healthy (n = 12) primary fibroblast lung cell lines were investigated for the expression of TANGO1. Histologic analyses for TANGO1 were performed on lung biopsy samples (n = 12 SSc patient samples and n = 8 healthy control samples).
RESULTS
SSc fibroblasts showed increased expression of TANGO1 protein in cultured fibroblasts. TANGO1 colocalizes with α-smooth muscle actin (α-SMA)-positive cells in SSc lung tissue and is highly up-regulated in the neointima of SSc vessels. TANGO1 expression was dependent on the inflammasome activation of caspase 1. It was also dependent on signaling from the interleukin-1 (IL-1) and transforming growth factor β (TGFβ) receptors. The decrease in TANGO1 down-regulated export of larger cargos including collagen and laminin. Reduced TANGO1 protein had no effect on smaller molecular weight cargoes; however, the secretion of elastin was significantly reduced.
CONCLUSION
TANGO1 is markedly increased in SSc fibroblasts and was found to be elevated in lung tissue in association with α-SMA-positive cells. TANGO1 expression is driven by inflammasome-dependent caspase 1 activation and is mediated by IL-1 and TGFβ downstream signaling. These observations suggest that during fibrosis, caspase 1 promotes the up-regulation of TANGO1 and the organization of endoplasmic reticulum exits sites, ultimately contributing to procollagen export and fibrosis.
Topics: Humans; Caspase 1; Endoplasmic Reticulum; Fibroblasts; Fibrosis; Inflammasomes; Interleukin-1; Procollagen; Scleroderma, Systemic; Transforming Growth Factor beta
PubMed: 37067501
DOI: 10.1002/art.42535 -
Proceedings of the National Academy of... Mar 2021Intracellular procollagen folding begins at the protein's C-terminal propeptide (C-Pro) domain, which initiates triple-helix assembly and defines the composition and...
Intracellular procollagen folding begins at the protein's C-terminal propeptide (C-Pro) domain, which initiates triple-helix assembly and defines the composition and chain register of fibrillar collagen trimers. The C-Pro domain is later proteolytically cleaved and excreted from the body, while the mature triple helix is incorporated into the extracellular matrix. The procollagen C-Pro domain possesses a single -glycosylation site that is widely conserved in all the fibrillar procollagens across humans and diverse other species. Given that the C-Pro domain is removed once procollagen folding is complete, the -glycan might be presumed to be important for folding. Surprisingly, however, there is no difference in the folding and secretion of -glycosylated versus non--glycosylated collagen type-I, leaving the function of the -glycan unclear. We hypothesized that the collagen -glycan might have a context-dependent function, specifically, that it could be required to promote procollagen folding only when proteostasis is challenged. We show that removal of the -glycan from misfolding-prone C-Pro domain variants does indeed cause serious procollagen and ER proteostasis defects. The -glycan promotes folding and secretion of destabilized C-Pro variants by providing access to the ER's lectin-based chaperone machinery. Finally, we show that the C-Pro -glycan is actually critical for the folding and secretion of even wild-type procollagen under ER stress conditions. Such stress is commonly incurred during development, wound healing, and other processes in which collagen production plays a key role. Collectively, these results establish an essential, context-dependent function for procollagen's previously enigmatic -glycan, wherein the carbohydrate moiety buffers procollagen folding against proteostatic challenge.
Topics: Collagen; Extracellular Matrix; Glycosylation; Humans; Procollagen; Protein Domains; Proteoglycans; Proteostasis
PubMed: 33674390
DOI: 10.1073/pnas.2026608118 -
American Journal of Transplantation :... Mar 2023Acute rejection (AR) is an important factor that leads to poor prognosis after liver transplantation (LT). Macrophage M1-polarization is an important mechanism in AR...
Acute rejection (AR) is an important factor that leads to poor prognosis after liver transplantation (LT). Macrophage M1-polarization is an important mechanism in AR development. MicroRNAs play vital roles in disease regulation; however, their effects on macrophages and AR remain unclear. In this study, rat models of AR were established following LT, and macrophages and peripheral blood mononuclear cells were isolated from rats and humans, respectively. We found miR-449a expression to be significantly reduced in macrophages and peripheral blood mononuclear cells. Overexpression of miR-449a not only inhibited the M1-polarization of macrophages in vitro but also improved the AR of transplant in vivo. The mechanism involved inhibiting the noncanonical nuclear factor-kappaB (NF-κB) pathway. We identified procollagen-lysine1,2-oxoglutarate5-dioxygenase 1 (PLOD1) as a target gene of miR-449a, which could reverse miR-449a's inhibition of macrophage M1-polarization, amelioration of AR, and inhibition of the NF-κB pathway. Overall, miR-449a inhibited the NF-κB pathway in macrophages through PLOD1 and also inhibited the M1-polarization of macrophages, thus attenuating AR after LT. In conclusion, miR-449a and PLOD1 may be new targets for the prevention and mitigation of AR.
Topics: Animals; Humans; Rats; Leukocytes, Mononuclear; Liver Transplantation; Macrophages; MicroRNAs; NF-kappa B; Procollagen
PubMed: 36695693
DOI: 10.1016/j.ajt.2022.12.009