Abnormal cellular copper levels have been clearly implicated in genetic diseases, cancer, and neurodegeneration. Ctr1, a high-affinity copper transporter, is a homotrimeric integral membrane protein ...that provides the main route for cellular copper uptake. Together with a sophisticated copper transport system, Ctr1 regulates Cu(I) metabolism in eukaryotes. Despite its pivotal role in normal cell function, the molecular mechanism of copper uptake and transport via Ctr1 remains elusive. In this study, electron paramagnetic resonance (EPR), UV-visible spectroscopy, and all-atom simulations were employed to explore Cu(I) binding to full-length human Ctr1 (hCtr1), thereby elucidating how metal binding at multiple distinct sites affects the hCtr1 conformational dynamics. We demonstrate that each hCtr1 monomer binds up to five Cu(I) ions and that progressive Cu(I) binding triggers a marked structural rearrangement in the hCtr1 C-terminal region. The observed Cu(I)-induced conformational remodeling suggests that the C-terminal region may play a dual role, serving both as a channel gate and as a shuttle mediating the delivery of copper ions from the extracellular hCtr1 selectivity filter to intracellular metallochaperones. Our findings thus contribute to a more complete understanding of the mechanism of hCtr1-mediated Cu(I) uptake and provide a conceptual basis for developing mechanism-based therapeutics for treating pathological conditions linked to de-regulated copper metabolism.
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A feeding trial was conducted to evaluate the dietary copper requirement of red drum (Sciaenops ocellatus) and compare the bioavailability of copper sulphate (CuSO4) and copper‐ethanolamine. A basal ...diet was formulated using semi‐purified ingredients and analysed to contain 3 mg Cu/kg. Both copper sources were supplemented to the basal diet at either 5, 10 or 20 mg Cu/kg of dry diet. No significant differences were observed in growth performance of fish fed the various diets. However, red drum fed all copper‐supplemented diets retained more copper in liver and whole‐body tissues compared to fish fed the basal diet. Within both inorganic and organic copper treatments, the highest tissue copper concentrations were observed in fish fed diets supplemented with 10 mg Cu/kg. No significant differences were detected in net copper retention regardless of the nature of the copper source; hence, the bioavailability of copper sulphate and copper‐ethanolamine complex was not different in the diets for juvenile red drum. Furthermore, the minimum copper requirement for growth performance of juvenile red drum appeared to be satisfied when fish were fed the basal diet containing 3 mg Cu/kg diet, and no detrimental effects were observed in red drum fed diets supplemented with 20 mg Cu/kg.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Wilson disease (WD) is an inherited disorder of copper metabolism that leads to copper accumulation and toxicity in the liver and brain. It is caused by mutations in the adenosine triphosphatase ...copper transporting β gene (ATP7B), which encodes a protein that transports copper from hepatocytes into the bile. We studied ATP7B-deficient cells and animals to identify strategies to decrease copper toxicity in patients with WD.
We used RNA-seq to compare gene expression patterns between wild-type and ATP7B-knockout HepG2 cells exposed to copper. We collected blood and liver tissues from Atp7b−/− and Atp7b+/− (control) rats (LPP) and mice; some mice were given 5 daily injections of an autophagy inhibitor (spautin-1) or vehicle. We obtained liver biopsies from 2 patients with WD in Italy and liver tissues from patients without WD (control). Liver tissues were analyzed by immunohistochemistry, immunofluorescence, cell viability, apoptosis assays, and electron and confocal microscopy. Proteins were knocked down in cell lines using small interfering RNAs. Levels of copper were measured in cell lysates, blood samples, liver homogenates, and subcellular fractions by spectroscopy.
After exposure to copper, ATP7B-knockout cells had significant increases in the expression of 103 genes that regulate autophagy (including MAP1LC3A, known as LC3) compared with wild-type cells. Electron and confocal microscopy visualized more autophagic structures in the cytoplasm of ATP7B-knockout cells than wild-type cells after copper exposure. Hepatocytes in liver tissues from patients with WD and from Atp7b−/− mice and rats (but not controls) had multiple autophagosomes. In ATP7B-knockout cells, mammalian target of rapamycin (mTOR) had decreased activity and was dissociated from lysosomes; this resulted in translocation of the mTOR substrate transcription factor EB to the nucleus and activation of autophagy-related genes. In wild-type HepG2 cells (but not ATP7B-knockout cells), exposure to copper and amino acids induced recruitment of mTOR to lysosomes. Pharmacologic inhibitors of autophagy or knockdown of autophagy proteins ATG7 and ATG13 induced and accelerated the death of ATP7B-knockout HepG2 cells compared with wild-type cells. Autophagy protected ATP7B-knockout cells from copper-induced death.
ATP7B-deficient hepatocytes, such as in those in patients with WD, activate autophagy in response to copper overload to prevent copper-induced apoptosis. Agents designed to activate this autophagic pathway might decrease copper toxicity in patients with WD.
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Dense Cu sub(2)ZnSnSe sub(4) (CZTSe) thin films with large grains of 1-6 mu m were prepared by sputtering a metallic Cu-Zn-Sn target followed by a selenization process at 600 degree C. Selenization ...of Cu-Zn-Sn metallic films with the aid of (SnSe sub(2)+Se) and CuSe sub(2) was explained, which involved the nucleation and growth stages. The design of modified Cu(In,Ga)Se sub(2) barrier layer prevented high-temperature reactions between the Mo electrode and as-deposited film and led to a pore-free interface. Using our simple approach, passivated and large grains were formed in an absorption layer, which is important for fabricating CZTSe solar cells.
•The growth was decreased with increasing of both forms of Cu doses.•Copper was increased in all tissues with increasing of both forms of Cu doses.•The remaining tissues and the liver contributed ...most of the total Cu in the body.•Either Cu-NPs or CuSO4 caused tissues oxidative stress and cell apoptosis.•Dissolved Cu was more toxic than Cu-NPs.
Copper nanoparticles (Cu-NPs) were widely used in various industrial and commercial applications. In this study the effects of Cu-NPs and soluble Cu were investigated on juvenile Epinephelus coioides. The fish were exposed in triplicate to control, 20 or 100μgCuL−1 as either copper sulphate (CuSO4) or Cu-NPs in a semi-static aqueous culture for 25 days. The growth parameters were significantly lower at 100μgCuL−1 as CuSO4 or Cu-NPs treatment compared to control. Time-dependent Cu accumulation in all tissues increased with increasing the Cu dose. The percentage of total Cu found in remaining tissues (head, bones, fins, etc.) decreased more in the CuSO4 than Cu-NPs treatment after 25 days, but increased in all other tissues (especially in liver). Compared with the control, either Cu-NPs or CuSO4 induced higher malonaldehyde concentration in tissues by overwhelming total superoxide dismutase activity, total glutathione concentration and Na+/K+-ATPase activity, but the opposite results were recorded for the brain. With increasing the CuSO4 or Cu-NPs dose, apoptosis was exacerbated in the liver and gills, more so by CuSO4 than Cu-NPs. Overall, these findings showed that Cu-NPs had the toxic effects similar to dissolved Cu; hence, Cu-NPs need to be included in the assessment of toxicological impacts in the aquatic environment.
Copper (Cu) is an essential micronutrient involved in a variety of fundamental biological processes. Recently, disorder of Cu homeostasis can be observed in many malignancies. Elevated Cu levels in ...serum and tissue are correlated with cancer progression. Hence, targeting Cu has emerged as a novel strategy in cancer treatment. This review provides an overview of physiological Cu metabolism and its homeostasis, followed by a discussion of the dysregulation of Cu homeostasis in cancer and the effects of Cu on cancer progression. Finally, recent therapeutic advances using Cu coordination complexes as anticancer agents, as well as the mechanisms of their anti‐cancer action are discussed. This review contributes full comprehension to the role of Cu in cancer and demonstrates the broad application prospect of Cu coordination compounds as potential therapeutic agents.
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Precise diagnosis of lymph node metastasis to guide lymphadenectomy is highly important for gastric cancer therapy in clinics. Though surgical dissection of regional metastatic lymph ...nodes remains the only way for gastric cancer therapy, the extended dissection may cause unavoidable postoperative risk of complications. It is still lack of effective method enabling the accurate removal of metastatic gastric cancer cells in lymph nodes with minimum injuries to normal tissue. Herein, we report a new fluorescent copper sulfide (CuS) nanoparticle (RGD-CuS-Cy5.5) enabling both non-invasive multimodality imaging and targeting photothermal therapy (PTT) of metastatic gastric cancer cells in lymph nodes. We demonstrate that RGD-CuS-Cy5.5 can easily drain into sentinel lymph nodes (SLN) after injection into primary tumors, and selectively enter into metastatic gastric MNK45 tumor cells via αvβ3 integrin-mediated endocytosis. The resulting strong near-infrared (NIR) fluorescence and computed tomography (CT) contrast in metastatic SLN compared to normal SLN can precisely differentiate SLN metastasis of gastric cancers. Guided by the imaging, localized PTT with RGD-CuS-Cy5.5 is conducted upon irradiation with an 808 nm laser, resulting in complete removal of metastatic gastric tumor cells in SLN without obvious toxicity. Moreover, RGD-CuS-Cy5.5 can also allow for the rapid and non-invasive self-monitoring of PTT efficacy against metastatic SLNs in living mice. This study highlights the potential of using RGD-CuS-Cy5.5 for imaging-guided and targeting PTT of SLN metastasis in vivo, which may be applicable for the metastatic gastric cancer therapy in clinics.
RGD-CuS-Cy5.5 nanoparticles possess NIR fluorescence and CT signals for in vivo bimodality imaging of lymph node metastasis. Strong photothermal property under irradiation at 808 nm for efficient PTT. Easy drain into sentinel lymph nodes and selective enter metastatic gastric cancer cells via αvβ3 integrin-mediated endocytosis. Rapid and non-invasive monitoring of therapeutic efficacy against lymph node metastasis.
This book provides fully updated coverage of the copper production process encompassing topics as diverse as environmental technology for wind and solar energy transmission, treatment of waste ...byproducts, and recycling of electronic scrap for potential alternative technology implementation. The authors examine industrially-grounded treatments of process fundamentals and the beneficiation of raw materials, smelting and converting, hydrometallurgical processes, and refining technology for a mine-to-market perspective, from primary and secondary raw materials extraction to shipping of rod or billet to customers. The modern coverage of the work includes bath smelting processes such as Ausmelt and Isasmelt which have become state-of-the-art in sulfide concentrate smelting and converting.
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