Serum Levels of Copper, Ceruloplasmin and Angiotensin Converting Enzyme among Silicotic and Non-Silicotic Workers

Beshir, Safia; Aziz, Hisham M.; Shaheen, Weam; Eltahlawy, Eman

doi:10.3889/oamjms.2015.065

Cited by 12 publications

(14 citation statements)

References 30 publications

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“…Therefore, we measured these peptides of the RAS in silicotic patients and compared them with those in non‐silicotic workers. Unfortunately, our findings were not in agreement with other studies (Beshir, Aziz, Shaheen, & Eltahlawy, ; Zielonka et al., ); we only found an increase in ACE in patients with silicosis phase III and an upregulation of Ang II in silicosis phase I. Furthermore, we also found that Ang‐(1–7) was elevated in silicosis phase II and Ac‐SDKP was increased in silicosis phase III compared with non‐silicotic patients.…”

Section: Discussioncontrasting

confidence: 98%

Interaction of N‐acetyl‐seryl‐aspartyl‐lysyl‐proline with the angiotensin‐converting enzyme 2–angiotensin‐(1–7)–Mas axis attenuates pulmonary fibrosis in silicotic rats

Gao

Zhang

et al. 2019

Experimental Physiology

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New Findings What is the central question of this study?What are the effects of the antifibrotic peptide acetyl‐seryl‐aspartyl‐lysyl‐proline (Ac‐SDKP) on the angiotensin‐converting enzyme 2 (ACE2)–angiotensin‐(1–7)–Mas axis during the occurrence and progression of silicosis? What is the main finding and its importance?Ac‐SDKP inhibited lung fibrosis in rats exposed to silica by activation of the ACE2–angiotensin‐(1–7)–Mas axis. Angiotensin‐(1–7) potentially promotes Ac‐SDKP by increasing the level of meprin α, the major synthetase of Ac‐SDKP. Thus, the interaction Ac‐SDKP and angiotesin‐(1–7) in silicosis could provide a new therapeutic strategy. Abstract The central role of angiotensin‐converting enzyme (ACE) in the occurrence and progression of silicosis has been established. The antifibrotic peptide acetyl‐seryl‐aspartyl‐lysyl‐proline (Ac‐SDKP) can be degraded by ACE. The ACE2–angiotensin‐(1–7)–Mas axis is protective and acts to counterbalance the detrimental effects of ACE–angiotensin II (Ang II)–Ang II type 1 receptor and exerts antifibrotic effects. Here, we demonstrate an interaction between Ac‐SDKP and Ang‐(1–7) in the inhibition of collagen deposition and myofibroblast differentiation in rats exposed to silica. Treatment with Ac‐SDKP increased the level of ACE2–Ang‐(1–7)–Mas in rats or in cultured fibroblasts and decreased the levels of collagen type I and α‐smooth muscle actin. Furthermore, exogenous Ang‐(1–7) had similar antifibrotic effects and increased the level of meprin α, a major Ac‐SDKP synthetase, both in vivo and in vitro. Compared with non‐silicotic patients exposed to silica, the level of serum ACE was increased in patients with silicosis phase III; the levels of Ang II and Ang‐(1–7) were high in patients with silicosis phase II; and the level of Ac‐SDKP was high in the silicosis phase III group. These data imply that Ac‐SDKP and Ang‐(1–7) have an interactive effect as regulatory peptides of the renin–angiotensin system and exert antifibrotic effects.

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Section: Discussioncontrasting

confidence: 98%

Interaction of N‐acetyl‐seryl‐aspartyl‐lysyl‐proline with the angiotensin‐converting enzyme 2–angiotensin‐(1–7)–Mas axis attenuates pulmonary fibrosis in silicotic rats

Gao

Zhang

et al. 2019

Experimental Physiology

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“…This situation was in reversed tendency after treatment with arctiin and arctigenin (Figures S2a-S2f). Serum lysozyme and ceruloplasmin were increased in dust-induced PF [30,31] because lysosomes in cells were damaged and released lysozymes to stimulate fibroblast proliferation after macrophages swallowed the dust [32]. Ceruloplasmin promoted amino oxidation of lysine in peptide chains and eventually resulted in the formation of collagen fibrosis [33].…”

Section: Resultsmentioning

confidence: 99%

The Ameliorative Effects of Arctiin and Arctigenin on the Oxidative Injury of Lung Induced by Silica via TLR‐4/NLRP3/TGF‐β Signaling Pathway

Liu

Wang

Dou

et al. 2021

Oxidative Medicine and Cellular Longevity

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Silicosis remains one of the most serious diseases worldwide, with no effective drug for its treatment. Our research results have indicated that arctiin and arctigenin could increase the mitochondrial membrane potential, which in turn reduces the production of reactive oxygen species (ROS), blocks the polarization of macrophages, and inhibits the differentiation of myofibroblasts to reduce oxidative stress, inflammation, and fibrosis. Further, our study revealed that arctiin and arctigenin suppressed the activation of NLRP3 inflammasome through the TLR-4/Myd88/NF-κB pathway and the silica-induced secretion of TNF-α, IL-1β, TGF-β, and α-SMA. Besides, the silica-induced increase in the levels of serum ceruloplasmin and HYP was also inhibited. Results of metabolomics indicated that arctiin and arctigenin could regulate the abnormal metabolic pathways associated with the development of silicosis, which involve pantothenate and CoA biosynthesis, cysteine and methionine metabolism, linoleic acid metabolism, and arginine and proline metabolism successively. Furthermore, the analysis of metabolomics, together with network topological analysis in different phases of silicosis, revealed that urine myristic acid, serum 4-hydroxyproline, and L-arginine could be regarded as diagnosis biomarkers in the early phase and formation of pulmonary fibrosis in the latter phases of silicosis. Arctiin and arctigenin could downregulate the increased levels of myristic acid in the early phase and serum 4-hydroxyproline in the latter phase of silicosis. Interestingly, the integration of TLR-4/NLRP3/TGF-β signaling and metabolomics verified the importance of macrophage polarization in the silicosis fibrosis process. To the best of our knowledge, this is the first study reporting that arctiin and arctigenin both can ameliorate silicosis effectively, and the former is a little stronger than its aglycone arctigenin because of its high oral bioavailability, low toxicity, and multimolecular active metabolites as determined by AdmetSAR and molecular docking analysis.

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“…1B). Similarly, several previous studies have reported that increased circulating levels of copper associate with fibrosis and organ damage (liver, lung, oral submucous tissue) in animals [3][4][5] and humans 18,19 ; however, the mechanism by which an elevated serum copper concentration leading to intracellular copper overload could induce organ fibrosis was not investigated in these studies.…”

Section: Discussionmentioning

confidence: 97%

Elevated intracellular copper contributes a unique role to kidney fibrosis by lysyl oxidase mediated matrix crosslinking

et al. 2020

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Copper ions play various roles in mammalian cells, presumably due to their involvement in different enzymatic reactions. Some studies indicated that serum copper correlates with fibrosis in organs, such as liver and lung. However, the mechanism is unknown. Here, we explored the role of copper in kidney fibrosis development and possible underlying mechanisms. We found that copper transporter 1 (CTR1) expression was increased in the kidney tissues in two fibrosis models and in patients with kidney fibrosis. Similar results were also found in renal tubular epithelial cells and fibroblast cells treated with transforming growth factor beta (TGF-β). Mechanistically, the upregulation of CTR1 required Smads-dependent TGF-β signaling pathway and Smad3 directly binded to the promoter of CTR1 in renal fibroblast cells using chromatin immunoprecipitation. Elevated CTR1 induced increase of copper intracellular influx. The elevated intracellular copper ions activated lysyl oxidase (LOX) to enhance the crosslinking of collagen and elastin, which then promoted kidney fibrosis. Reducing intracellular copper accumulation by knocking down CTR1 ameliorated kidney fibrosis in unilateral ureteral obstruction induced renal fibrosis model and renal fibroblast cells stimulated by TGF-β. Treatment with copper chelator tetrathiomolybdate (TM) also alleviated renal fibrosis in vivo and in vitro. In conclusion, intracellular copper accumulation plays a unique role to kidney fibrosis by activating LOX mediated collagen and elastin crosslinking. Inhibition of intracellular copper overload may be a potential portal to alleviate kidney fibrosis.

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Serum Levels of Copper, Ceruloplasmin and Angiotensin Converting Enzyme among Silicotic and Non-Silicotic Workers

Cited by 12 publications

References 30 publications

Interaction of N‐acetyl‐seryl‐aspartyl‐lysyl‐proline with the angiotensin‐converting enzyme 2–angiotensin‐(1–7)–Mas axis attenuates pulmonary fibrosis in silicotic rats

Interaction of N‐acetyl‐seryl‐aspartyl‐lysyl‐proline with the angiotensin‐converting enzyme 2–angiotensin‐(1–7)–Mas axis attenuates pulmonary fibrosis in silicotic rats

The Ameliorative Effects of Arctiin and Arctigenin on the Oxidative Injury of Lung Induced by Silica via TLR‐4/NLRP3/TGF‐β Signaling Pathway

Elevated intracellular copper contributes a unique role to kidney fibrosis by lysyl oxidase mediated matrix crosslinking

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