In Alzheimer\'s disease (AD), reactive oxygen species (ROS) plays a crucial role, which is produced from molecular oxygen with extracellular deposited amyloid-β (Aβ) aggregates through the reduction of a Cu2+ ion. In the presence of a small amount of redox-active Cu2+ ion, ROS is produced by the Aβ-Cu2+ complex as Aβ peptide alone is unable to generate excess ROS. Therefore, Cu2+ ion chelators are considered promising therapeutics against AD. Here, we have designed and synthesized a series of Schiff base derivatives (SB) based on 2-hydroxy aromatic aldehyde derivatives and dopamine. These SB compounds contain one copper chelating core, which captures the Cu2+ ions from the Aβ-Cu2+ complex. Thereby, it inhibits copper-induced amyloid aggregation as well as amyloid self-aggregation. It also inhibits copper-catalyzed ROS production through sequestering of Cu2+ ions. The uniqueness of our designed ligands has the dual property of dopamine, which not only acts as a ROS scavenger but also chelates the copper ion. The crystallographic analysis proves the power of the dopamine unit. Therefore, dual exploration of dopamine core can be considered as potential therapeutics for future AD treatment.

Copper, an indispensable micronutrient, is implicated in numerous vital biological processes and is essential for all physiological activities. Recently, the discovery of a novel type of copper-dependent cell death, known as cuproptosis, has shed light on its role in cancer development. Extensive research is currently underway to unravel the mechanisms underlying cuproptosis and its correlation with various cancer types. In this review, we summarize the findings regarding the roles and mechanisms of cuproptosis in various cancer types, including colorectal cancer, lung cancer, gastric cancer, breast cancer, liver cancer and cutaneous melanoma. Furthermore, the effects of copper-related agents such as copper chelators and copper ionophores on cell proliferation, apoptosis, angiogenesis, tumor immunity, and chemotherapy resistance have been explored in cancer preclinical and clinical trials. These insights provide promising avenues for the development of prospective anticancer drugs aimed at inducing cuproptosis.

Radiation therapy is a first-line treatment for head and neck cancer; however, it typically leads to hyposalivation stemming from fibrosis of the salivary gland. Current strategies to restore glandular function are dependent on the presence of residual functional salivary gland tissue, a condition commonly not met in patients with extensive fibrotic coverage of the salivary gland resulting from radiation therapy. Fibrosis is defined by the pathological accumulation of connective tissue (i.e., extracellular matrix) and excessive deposition of crosslinked (fibrillar) collagen that can impact a range of tissues and given that collagen crosslinking is necessary for fibrosis formation, inhibiting this process is a reasonable focus for developing anti-fibrotic therapies. Collagen crosslinking is catalyzed by the lysyl oxidase family of secreted copper-dependent metalloenzymes, and since that copper is an essential cofactor in all lysyl oxidase family members, we tested whether localized delivery of a copper chelator into the submandibular gland of irradiated mice could suppress collagen deposition and preserve the structure and function of this organ. Our results demonstrate that transdermal injection of tetrathiomolybdate into salivary glands significantly reduced the early deposition of fibrillar collagen in irradiated mice and preserved the integrity and function of submandibular gland epithelial tissue. Together, these studies identify copper metabolism as a novel therapeutic target to control radiation induced damage to the salivary gland and the current findings further indicate the therapeutic potential of repurposing clinically approved copper chelators as neoadjuvant treatments for radiation therapy.

(1) Background: In patients with Wilson\'s disease, the deficiency of the copper carrier ATP7B causes the accumulation of copper in the liver, brain and various other organs. Lifelong treatment is therefore mandatory, using copper chelators to increase the excretion of copper and to avoid life-threatening damage. The clinically used reference drug, D-penicillamine, exhibit numerous adverse effects, especially a frequent severe and irreversible neurological worsening, mainly due to its lack of metal selectivity; (2) Methods: A new tetradentate ligand based on an 8-aminoquinoline entity, named TDMQ20, which is highly selective for copper compared with other metal ions, is evaluated in \"toxic milk\" TX mice as an oral treatment of this Wilson\'s disease murine model; (3) Results: The concentration of copper in the liver of \"toxic milk\" TX mice decreased and the fecal excretion of copper increased upon oral treatment with TDMQ20. Both effects are dose-dependent, and more pronounced than those of D-penicillamine; (4) Conclusions: The TDMQ20 copper chelator is more efficient than the reference drug D-penicillamine for the treatment of a Wilson\'s disease murine model. Pharmacological data obtained with TDMQ20 on the TX mouse model strongly support the selection of this ligand as a drug candidate for this genetic disease.

UNASSIGNED: Hepatocellular carcinoma (HCC) is one of the main cancer-related mortality worldwide. Thus, there is a constant search for improvement in treatment strategies to enhance the prognosis of this malignancy. The study aims to investigate the combined antitumor activity of ammonium tetrathiomolybdate (TM, copper chelator) combined with hepatic artery ligation (HAL) for liver cancer.
UNASSIGNED: A total of 40 Sprague-Dawley (SD) rats bearing hepatic tumors were randomly divided into four groups: the control group without any treatment (control), HAL only (HAL), given TM by gavage (TM), and given TM combined with HAL (HAL + TM). The concentrations of serum copper were measured at the predetermined time points. Tumor growth rate, overall survival (OS), expression of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and microvessel density (MVD), as determined by immunohistochemical examination, were compared.
UNASSIGNED: HAL treatment transiently could elevate alanine transaminase (ALT) and aspartate transaminase (AST) but resumed to baseline within 1 week. Serum copper was significantly increased in tumor-bearing animals over time. The values of serum copper in the three treatment groups were significantly lower than those in the control group at different time points, with the lowest values observed in the TM group (P < .05). The average tumor size was 30.33 ± 2.58, 20.83 ± 2.93, 16.80 ± 3.84, and 10.88 ± 1.08 mm in the control, HAL, TM, and HAL + TM groups, respectively (HAL + TM vs other groups, all P < .05). In addition, the expression levels of HIF-1α, VEGF, and MVD were significantly lower in the HAL + TM group than those in the other groups (P < .05). The OS of rats in the combined groups was significantly prolonged combined to the other groups (P < .05), with survival time of 19.1 ± 0.64, 25.4 ± 1.24, 25.3 ± 1.78, and 29.9 ± 2.22 days in the control, HAL, TM, and HAL + TM groups, respectively.
UNASSIGNED: These findings suggest that combined treatment with TM and HAL holds great potential for liver cancer treatment by reducing tumor hypoxia and angiogenesis. The observed results indicate that these combinations may offer a novel target and strategy for interventional therapy of liver cancer.

Copper is an essential trace metal for normal cellular functions; a lack of copper is reported to impair the function of important copper-binding enzymes, while excess copper could lead to cell death. Numerous studies have shown an association between dietary copper consumption or plasma copper levels and the incidence of diabetes/diabetes complications. And experimental studies have revealed multiple signaling pathways that are triggered by copper shortages or copper overload in diabetic conditions. Moreover, studies show that treated with copper chelators improve vascular function, maintain copper homeostasis, inhibit cuproptosis, and reduce cell toxicity, thereby alleviating diabetic neuropathy, retinopathy, nephropathy, and cardiomyopathy. However, the mechanisms reported in these studies are inconsistent or even contradictory. This review summarizes the precise and tight regulation of copper homeostasis processes, and discusses the latest progress in the association of diabetes and dietary copper/plasma copper. Further, the study pays close attention to the therapeutic potential of copper chelators and copper in diabetes and its complications, and hopes to provide new insight for the treatment of diabetes.

Copper ions play a crucial role in the progression of cancers. Tumor tissue is rich in copper ions, and copper chelators could potentially scavenge these copper ions and thus exert an antitumor effect. In this study, we report the synthesis of a novel thieno[3,2-c]pyridine compound we have called \"JYFY-001\" that can act as the copper chelator thanks to the inclusion of an N-(pyridin-2-yl)acetamide moiety that targets copper ions. JYFY-001 potently inhibited cancer proliferation, inducing cell apoptosis and impairing the extracellular acidification rate and oxygen consumption rate of colorectal cancer (CRC) cells. JYFY-001 also inhibited the growth of a CRC-transplanted tumor in a dose-dependent manner, inducing apoptosis of the tumor cells and promoting the infiltration of lymphocytes in the CRC-transplanted tumor tissues. JYFY-001 also enhanced the antitumor effects of the programmed cell death protein 1 (PD-1) inhibitor. The relatively benign nature of JYFY-001 was demonstrated by the effect on normal cell viability and acute toxicity tests in mice. Our findings suggest that JYFY-001 is a prospective copper chelator to be used as a targeted drug and a synergist of immunotherapy for CRC treatments.

(1) Background: TDMQ20 is a specific regulator of copper homeostasis in the brain, able to inhibit cognitive impairment in the early stages of Alzheimer\'s disease (AD) in mouse models of AD. To promote the further development of this drug-candidate, preliminary data on the pharmacokinetics of TDMQ20 in a mammal model have been collected. Since TDMQ20 should be administered orally, its absorption by the gastrointestinal tract was evaluated by comparison of blood concentrations after administration by oral and IV routes, and its ability to reach its target (the brain) was confirmed by comparison between blood and brain concentrations after oral administration. (2) Methods: plasmatic and brain concentrations of the drug after oral or intravenous treatment of rats at pharmacologically relevant doses were determined as a function of time. (3) Results: oral absorption of TDMQ20 was rapid and bioavailability was high (66% and 86% for males and females, respectively). The drug accumulated in the brain for several hours (brain-plasma ratio 3 h after oral administration = 2.6), and was then efficiently cleared. (4) Conclusions: these data confirm that TDMQ20 efficiently crosses the brain-blood barrier and is a relevant drug-candidate to treat AD.

The interaction between copper ions and amyloid peptide Aβ has been reported to be involved in Alzheimer\'s disease (AD) pathology. Based on copper coordination biochemistry, we designed specific copper chelators [tetradentate monoquinolines (TDMQs)] in order to regulate copper homeostasis in the AD brain and inhibit the deleterious oxidative stress catalyzed by copper-Aβ complexes. We previously reported that TDMQ20, a highly selective copper chelator selected as a drug candidate, was able to extract copper from the Cu-Aβ1-16 complex and restore cognitive and behavioral deficits in AD mouse models. For a better understanding of the mechanism of action of TDMQ20, we decided to investigate the change of profile of proteins expressed in 5xFAD mice after an oral treatment of TDMQ20 (dose = 10 mg/kg, once every two days for 3 months, in total 45 times). Clioquinol (CQ), a non-specific chelator, has been used as a comparator. Here, we report the proteomic alterations in the cortex of 5xFAD mice using iTRAQ (isobaric tags for relative and absolute quantification) proteomics technology. The results indicated that 178 differentially expressed proteins (DEPs) have been identified in the AD mouse group with respect to wild type (WT) animals (AD/WT). After treatment by TDMQ20, 35 DEPs were found common in AD/WT and TDMQ20/AD groups in an opposite change manner (up- or down-regulated, respectively). In addition, among the 35 DEPs mentioned above, 10 common target proteins have been identified in AD/WT, TDMQ20/AD, and CQ/AD groups, among which 3 target proteins were successfully validated by western blot analysis. In particular, the expression levels of ChAT and CHRM4 are significantly increased upon TDMQ20 treatment with respect to 5xFAD mice, while CQ did not significantly change the expression of these proteins. Our study suggests the involvement of the copper chelator TDMQ20 on the cholinergic system, a feature that may explain the improved cognitive and behavioral performance in AD mice upon oral treatment of TDMQ20.

The study aims to investigate the suppressing tumor-promoting effects via multi-anti-angiogenesis activity of the copper chelator (ammonium tetrathiomolybdate, TM) combined with lenvatinib for hepatocellular carcinoma.
A total of 55 C57 mice were injected subcutaneously with Hepa1-6 hepatoma cell suspensions into the right posterior thigh. After 7 days, the subcutaneous tumors were formed, and the mice were randomly divided into five groups: TM (G1), Lenvatinib (G2), TM+Lenvatinib (G3), Control (G4), and Copper (II) Gluconate (G5). The copper concentrations in serum and tumors were measured at the predetermined time points. After 14 days of treatments, tumor weight and volumes were analyzed, histology was observed, and the expressions of vascular endothelial growth factor (VEGF) and microvessel density (MVD) in tumor tissues were measured by immunohistochemistry.
The median concentration of copper in serum was 401.70, 469.40, and 665.35 μg/L in normal mice, in mice 7 days after implantation, and in the control group, respectively. The intratumoral copper concentrations were higher in G4 mice than in mice 7 days after implantation (P < 0.05). The serum concentration of copper was higher in G5 than all the other groups (P < 0.05; (G1, G2, and G3) vs. G4, P < 0.05; G1 vs. G2, P = 0.013; G2 vs. G3, P = 0.018; G1 vs. G3, P = 0.903. The intratumoral copper concentrations were 608.40, 980.00, 539.31, and 2938.90 μg/L in G1, G2, G3, and G5, respectively. The average tumor weight was 0.55, 0.44, 0.08, 1.37, and 3.11 in G1, G2, G3, G4, and G5, respectively. G5 vs. other groups, P < 0.05; (G1, G2, and G3) vs. G4, P < 0.05; G1 vs. G3, P < 0.05; G2 vs. G3, P < 0.05; G1 vs. G2, P > 0.05. Furthermore, the expression levels of VEGF were significantly lower in G1, G2, and G3 than in G4 and G5 (P < 0.05). A similar trend was observed for MVD in the five groups, but no significant difference was detected in G1 and G2.
The study showed a significant positive correlation between tumor load and copper. Copper promotes tumor progression, but copper chelating suppresses tumor growth. The combination of TM with lenvatinib reduces tumor angiogenesis and improves the effect of antitumor treatment. These findings underlie the clinical application of combination therapy.