Imbalanced and Unchecked: The Role of Metal Dyshomeostasis in Driving COPD Progression.

Chronic obstructive pulmonary disease (COPD) is a chronic respiratory condition characterized by persistent inflammation and oxidative stress, which ultimately leads to progressive restriction of airflow. Extensive research findings have cogently suggested that the dysregulation of essential transition metal ions, notably iron, copper, and zinc, stands as a critical nexus in the perpetuation of inflammatory processes and oxidative damage within the lungs of COPD patients. Unraveling the intricate interplay between metal homeostasis, oxidative stress, and inflammatory signaling is of paramount importance in unraveling the intricacies of COPD pathogenesis. This comprehensive review aims to examine the current literature on the sources, regulation, and mechanisms by which metal dyshomeostasis contributes to COPD progression. We specifically focus on iron, copper, and zinc, given their well-characterized roles in orchestrating cytokine production, immune cell function, antioxidant depletion, and matrix remodeling. Despite the limited number of clinical trials investigating metal modulation in COPD, the advent of emerging methodologies tailored to monitor metal fluxes and gauge responses to chelation and supplementation hold great promise in unlocking the potential of metal-based interventions. We conclude that targeted restoration of metal homeostasis represents a promising frontier for ameliorating pathological processes driving COPD progression.

Activate the endogenous Cu2+ switch for Zn(DDC)2 liposomes conversion: Providing a safer and less toxic alternative in cancer therapy.

The ancient anti-alcohol drug disulfiram (DSF) has gained widespread attention for its highly effective anti-tumor effects in cancer treatment. Our previous studies have developed liposome of Cu (DDC)2 to overcome the limitations, like the poor water solubility. However, Cu (DDC)2 liposomes still have shown difficulties in severe hemolytic reactions at high doses and systemic toxicity, which have limited their clinical use. Therefore, this study aims to exploratively investigate the feasibility of using DSF or DDC in combination also can chelate Zn2+ to form zinc diethyldithiocarbamate (Zn (DDC)2). Furthermore, this study prepared stable and homogeneous Zn (DDC)2 liposomes, which were able to be released in the tumor microenvironment (TME). The released Zn (DDC)2 was converted to Cu (DDC)2 with the help of endogenous Cu2+-switch enriched in the TME, which has a higher stability constant compared with Zn (DDC)2. In other words, the Cu2+-switch is activated at the tumor site, completing the conversion of the less cytotoxic Zn (DDC)2 to the more cytotoxic Cu (DDC)2 for effective tumor therapy so that the Zn (DDC)2 liposomes in vivo achieved the comparable therapeutic efficacy and provided a safer alternative to Cu (DDC)2 liposomes in cancer therapy.

How important are elements in polycystic ovary syndrome? Should they be supplemented? A systematic review.

Polycystic ovary syndrome (PCOS) is a multifactorial disorder with unknown etiology. The purpose of this systematic review is to analyze the available clinical trials on elemental supplementation in terms of improving biochemical parameters in women with PCOS. Electronic databases were searched from their inception until February 2023. Randomized controlled trials (RCTs) of PCOS during therapy with elemental supplementation alone or in combination with other elements were analyzed. Recommendations regarding supplementation with elements are not clear. There are many factors to consider, with the primary factor being the type of element and the possibility of supplementation and a balanced diet. Another aspect to consider is the presence of comorbidities, which may increase the demand for and absorption of elements. A final factor to be considered is the determination of the body's need for specific elements. Some elements may require supplementation (e.g., magnesium, selenium, iodine, calcium), while others (e.g., iron, copper, potassium, zinc, manganese, chromium) are in sufficient amounts in a proper diet, and some should be limited (e.g., sodium, phosphorus). It is necessary to determine the optimal dose of each element in order to improve the biochemical parameters of PCOS as much as possible, while at the same time avoiding the negative effects of excessive consumption.

A biomimetic cuproptosis amplifier for targeted NIR-II fluorescence/photoacoustic imaging-guided synergistic NIR-II photothermal immunotherapy.

The therapeutic efficacy of cuproptosis combined with phototheranostics is still hindered by easy copper efflux, nonspecific accumulation and limited light penetration depth. Here, a high-performance NIR-II semiconductor polymer was first synthesized through dual-donor engineering. Then a biomimetic cuproptosis amplifier (PCD@CM) was prepared by Cu(II)-mediated coordinative self-assembly of NIR-II ultrasmall polymer dots and the chemotherapeutic drug DOX, followed by camouflaging of tumor cell membranes. After homologous targeting delivery to tumor cells, overexpressed GSH in the tumor microenvironment (TME) triggers the disassembly of the amplifier and the release of therapeutic components through the reduction of Cu(II) to Cu(I), which enable NIR-II fluorescence/photoacoustic imaging-guided NIR-II photothermal therapy (PTT) and chemotherapy. The released Cu(I) induces the aggregation of lipoylated mitochondrial proteins accompanied by the loss of iron-sulfur proteins, leading to severe proteotoxic stress and eventually cuproptosis. NIR-II PTT and GSH depletion render tumor cells more sensitive to cuproptosis. The amplified cuproptosis sensitization provokes significant immune surveillance, triggering the immunogenic cell death (ICD) to promote cytotoxic T lymphocyte infiltration together with aPD-L1-mediated immune checkpoint blockade. This work proposes a new strategy to develop cuproptosis sensitization systems enhanced by NIR-II phototheranostics with homologous targeting and anti-tumor immune response capabilities.

Recent advances in copper sulfide nanoparticles for phototherapy of bacterial infections and cancer.

Copper sulfide nanoparticles (CuS NPs) have attracted growing interest in biomedical research due to their remarkable properties, such as their high photothermal and thermodynamic capabilities, which are ideal for anticancer and antibacterial applications. This comprehensive review focuses on the current state of antitumor and antibacterial applications of CuS NPs. The initial section provides an overview of the various approaches to synthesizing CuS NPs, highlighting the size, shape and composition of CuS NPs fabricated using different methods. In this review, the mechanisms underlying the antitumor and antibacterial activities of CuS NPs in medical applications are discussed and the clinical challenges associated with the use of CuS NPs are also addressed.

Codelivery of CuS and DOX into Deep Tumors with Size and Charge-Switchable PAMAM Dendrimers for Chemo-photothermal Therapy.

Accurate targeting of therapeutic agents to specific tumor tissues, especially via deep tumor penetration, has been an effective strategy in cancer treatments. Here, we described a flexible nanoplatform, pH-responsive zwitterionic acylsulfonamide betaine-functionalized fourth-generation PAMAM dendrimers (G4-AB), which presented multiple advantages for chemo-photothermal therapy, including template synthesis of ultrasmall copper sulfide (CuS) nanoparticles and further encapsulation of doxorubicin (DOX) (G4-AB-DOX/CuS), long-circulating performance by a relatively large size and zwitterionic surface in a physiological environment, combined size shrinkage, and charge conversions via pH-responsive behavior in an acidic tumor microenvironment (TME). Accordingly, high tumor penetration and positive cell uptake for CuS and DOX have been determined, which triggered an excellent combination treatment under near-infrared irradiation in comparison to the monochemotherapy system and irresponsive chemo-photothermal system. Our study represented great promise in constructing multifunctional carriers for the effective delivery of photothermal nanoparticles and drugs in chemo-photothermal therapy.

Widespread selenium deficiency in the brain of cases with Huntington's disease presents a new potential therapeutic target.

BACKGROUND: Huntington or Huntington's disease (HD) is an autosomal dominant neurodegenerative disease characterised by both progressive motor and cognitive dysfunction; its pathogenic mechanisms remain poorly understood and no treatment can currently slow, stop, or reverse its progression. There is some evidence of metallomic dysfunction in limited regions of the HD brain; we hypothesised that these alterations are more widespread than the current literature suggests and may contribute to pathogenesis in HD. METHODS: We measured the concentrations of eight essential metals (sodium, potassium, magnesium, calcium, iron, zinc, copper, and manganese) and the metalloid selenium across 11 brain regions in nine genetically confirmed, clinically manifest cases of HD and nine controls using inductively-coupled plasma mass spectrometry. Case-control differences were assessed by non-parametric Mann-Whitney U test (p < 0.05), risk ratios, E-values, and effect sizes. FINDINGS: We observed striking decreases in selenium levels in 11 out of 11 investigated brain regions in HD, with risk ratios and effect sizes ranging 2.3-9.0 and 0.7-1.9, respectively. Increased sodium/potassium ratios were observed in every region (risk ratio = 2.5-8.0; effect size = 1.2-5.8) except the substantia nigra (risk ratio = 0.25; effect size = 0.1). Multiple regions showed increased calcium and/or zinc levels, and localised decreases in iron, copper, and manganese were present in the globus pallidus, cerebellum, and substantia nigra, respectively. INTERPRETATION: The observed metallomic alterations in the HD brain may contribute to several pathogenic mechanisms, including mitochondrial dysfunction, oxidative stress, and blood-brain barrier dysfunction. Selenium supplementation may represent a potential, much-needed therapeutic pathway for the treatment of HD that would not require localised delivery in the brain due to the widespread presence of selenium deficiency in regions that show both high and low levels of neurodegeneration. FUNDING: In Acknowledgments, includes the Lee Trust, the Endocore Research Trust, Cure Huntington's Disease Initiative, the Oakley Mental Health Research Foundation, the Medical Research Council (MRC), the New Zealand Neurological Foundation, and others.

Evaluation of vitamin B6 supplementation in Wilson's disease patients treated with D-penicillamine.

INTRODUCTION: Wilson's disease (WD) is a copper metabolism disorder characterised by a progressive accumulation of this metal mainly in the liver and the brain. Treatment is based on the removal of copper operated by the chelators, among which, D-penicillamine (DP) is prescribed as a first-line treatment in most situations. There is some evidence in linking the use of DP with a risk of vitamin B6; therefore, vitamin supplementation is sometimes recommended, although non-consensually. The objective of our study was to evaluate the level of vitamin B6 in WD patients treated with DP with and without associated supplementation. METHODOLOGY: All WD patients followed at the National Reference Centre for WD in Lyon between January 2019 and December 2020 treated with DP for more than 1 year were included and separated in two groups according to vitamin B6 supplementation. The level of vitamin B6 was measured by the determination of pyridoxal phosphate (PLP). RESULTS: A total of 37 patients were included. Average age of 23.3±14.8 years, 15 patients with <18 years. Median duration of treatment was 51 (55.8) months. 15 patients were under vitamin B6 supplementation and 22 had interrupted it for more than 1 year. The median PLP level was significantly higher in the group with supplementation, 137.2 (86.7) nmol/L vs 64.9 (30.8) nmol/(p<0.01). No patient had a PLP level<35 nmol/L. CONCLUSION: Long-term stable WD patients under DP treatment probably do not need vitamin B6 supplementation.

D-penicillamine-associated neutropenia in a Doberman pinscher.

Copper-associated hepatitis in dogs results from elevated copper levels secondary to increased intake or decreased clearance. Treatment is through establishing a negative copper balance and can include chelation therapy. Traditionally, chelation therapy in dogs is uses D-penicillamine, which has been shown to have severe side effects in humans. Side effects have not been well-documented in dogs but can include nephrotoxicity and dermatologic reactions. This article is the first to report neutropenia in a dog secondary to chelation therapy using D-penicillamine. In this case, a complete blood (cell) count (CBC) collected before initiation of chelation therapy was normal and neutropenia was documented 4 mo after starting therapy. A cytologic examination of bone marrow confirmed a myeloid hypoplasia. Following discontinuation of D-penicillamine, the neutropenia resolved. Based on this case report, periodic CBC rechecks following the initiation of D-penicillamine chelation therapy are recommended to guide treatment decisions. Key clinical message: Dogs with confirmed copper-associated hepatitis should be treated cautiously with D-penicillamine for chelation therapy. D-penicillamine may adversely affect bone marrow, causing a leukopenia characterized by neutropenia. It is recommended that clinicians periodically monitor neutrophil counts while treating dogs with D-penicillamine.

Neutropénie associée à la D-pénicillamine chez un Doberman pinscher. L'hépatite associée au cuivre chez le chien résulte de niveaux élevés de cuivre secondaires à une augmentation de l'apport ou à une diminution de la clairance. Le traitement consiste à établir un bilan négatif du cuivre et peut inclure une thérapie par chélation. Traditionnellement, la thérapie par chélation chez le chien utilise la D-pénicillamine, dont il a été démontré qu'elle a de graves effets secondaires chez l'homme. Les effets secondaires n'ont pas été bien documentés chez les chiens, mais peuvent inclure une néphrotoxicité et des réactions dermatologiques. Cet article est le premier à rapporter une neutropénie chez un chien secondaire à un traitement par chélation utilisant la D-pénicillamine. Dans ce cas, une numération globulaire complète (CBC) recueillie avant le début du traitement par chélation était normale et une neutropénie a été documentée 4 mois après le début du traitement. Un examen cytologique de la moelle osseuse a confirmé une hypoplasie myéloïde. Après l'arrêt de la D-pénicillamine, la neutropénie a disparu. Sur la base de ce rapport de cas, des vérifications périodiques de la CBC après le début du traitement par chélation de la D-pénicillamine sont recommandées pour guider les décisions de traitement.Message clinique clé :Les chiens atteints d'hépatite associée au cuivre confirmée doivent être traités avec prudence avec de la D-pénicillamine pour le traitement par chélation. La D-pénicillamine peut affecter négativement la moelle osseuse, provoquant une leucopénie caractérisée par une neutropénie. Il est recommandé aux cliniciens de surveiller périodiquement le nombre de neutrophiles lors du traitement des chiens avec de la D-pénicillamine.(Traduit par Dr Serge Messier).

Polymer/copper nanocomplex-induced lysosomal cell death promotes tumor lymphocyte infiltration and synergizes anti-PD-L1 immunotherapy for triple-negative breast cancer.

Our previous research discovered that combining the PDA-PEG polymer with copper ions can selectively kill cancer cells. However, the precise mechanism by which this combination functions was not fully understood. This study revealed that the PDA-PEG polymer and copper ions form complementary PDA-PEG/copper (Poly/Cu) nanocomplexes by facilitating copper ion uptake and lysosomal escape. An in vitro study found that Poly/Cu killed 4T1 cells through a lysosome cell death pathway. Furthermore, Poly/Cu inhibited both the proteasome function and autophagy pathway and induced immunogenic cell death (ICD) in 4T1 cells. The Poly/Cu induced ICD coupled with the checkpoint blockade effect of the anti-PD-L1 antibody (aPD-L1) synergistically promoted immune cell penetration into the tumor mass. Benefiting from the tumor-targeting effect and cancer cell-selective killing effect of Poly/Cu complexes, the combinatory treatment of aPD-L1 and Poly/Cu effectively suppressed the progression of triple-negative breast cancer without inducing systemic side effects.

Integrated Metabolomics and Network Pharmacology to Reveal the Mechanisms of Gandouling Tablets Against Copper-Overload-Induced Neuronal Injury in Rats with Wilson's Disease.

Purpose: Gandouling Tablets (GDL), a proprietary Chinese medicine, have shown a preventive effect against Wilson's disease (WD)-induced neuronal damage in previous studies. However, the potential mechanisms need additional investigation. Combining metabonomics and network pharmacology revealed the GDL pathway against WD-induced neuronal damage. Methods: The WD rat model with a high copper load was developed, and nerve damage was assessed. Total metabonomics was used to identify distinct hippocampus metabolites and enriched metabolic pathways in MetaboAnalyst. The GDL's possible targets against WD neuron damage were then determined by network pharmacology. Cytoscape constructed compound metabonomics and pharmacology networks. Moreover, molecular docking and Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR) validated key targets. Results: GDL reduced WD-induced neuronal injury. Twenty-nine GDL-induced metabolites may protect against WD neuron injury. According to network pharmacology, we identified three essential gene clusters, of which genes in cluster 2 had the most significant impact on the metabolic pathway. A comprehensive investigation identified six crucial targets, including UGT1A1, CYP3A4, CYP2E1, CYP1A2, PIK3CB, and LPL, and their associated core metabolites and processes. Four targets reacted strongly with GDL active components. GDL therapy improved five targets' expression. Conclusion: This collaborative effort revealed the mechanisms of GDL against WD neuron damage and a way to investigate the potential pharmacological mechanisms of other Traditional Chinese Medicine (TCM).

Membranous nephropathy caused by dimercaptosuccinic acid in a patient with Wilson's disease: a case report and literature review.

BACKGROUND: Dimercaptosuccinic acid (DMSA) therapy is a kind of chelation therapy for patients with Wilson 's disease (WD). While there have been reports of side effects associated with DMSA, the development of membranous nephropathy as a result of this therapy is uncommon. CASE PRESENTATION: We present a case of a 19-year-old male patient with Wilson's disease who experienced proteinuria while receiving long-term DMSA treatment. Further evaluation revealed abnormally low levels of serum ceruloplasmin and serum albumin, as well as a 24-hour urinary protein excretion of 4599.98 mg/24 h. A renal biopsy confirmed the presence of membranous nephropathy. After ruling out other potential causes, we determined that the patient's membranous nephropathy was likely caused by DMSA. Following treatment with glucocorticoids, there was a significant reduction in proteinuria. CONCLUSION: This case highlights the possibility of DMSA-induced membranous nephropathy and the importance of considering this diagnosis in patients receiving DMSA treatment. Given the widespread use of DMSA in the treatment of Wilson's disease, further research is needed to fully understand the potential role of this drug in the development of membranous nephropathy.

AKT-driven epithelial-mesenchymal transition is affected by copper bioavailability in HER2 negative breast cancer cells via a LOXL2-independent mechanism.

BACKGROUND: The main mechanism underlying cancer dissemination is the epithelial to mesenchymal transition (EMT). This process is orchestrated by cytokines like TGFß, involving "non-canonical" AKT- or STAT3-driven pathways. Recently, the alteration of copper homeostasis seems involved in the onset and progression of cancer. METHODS: We expose different breast cancer cell lines, including two triple negative (TNBC) ones, an HER2 enriched and one cell line representative of the Luminal A molecular subtype, to short- or long-term copper-chelation by triethylenetetramine (TRIEN). We analyse changes in the expression of EMT markers (E-cadherin, fibronectin, vimentin and αSMA), in the levels and activity of extracellular matrix components (LOXL2, fibronectin and MMP2/9) and of copper homeostasis markers by Western blot analyses, immunofluorescence, enzyme activity assays and RT-qPCR. Boyden Chamber and wound healing assays revealed the impact of copper chelation on cell migration. Additionally, we explored whether perturbation of copper homeostasis affects EMT prompted by TGFß. Metabolomic and lipidomic analyses were applied to search the effects of copper chelation on the metabolism of breast cancer cells. Finally, bioinformatics analysis of data on breast cancer patients obtained from different databases was employed to correlate changes in kinases and copper markers with patients' survival. RESULTS: Remarkably, only HER2 negative breast cancer cells differently responded to short- or long-term exposure to TRIEN, initially becoming more aggressive but, upon prolonged exposure, retrieving epithelial features, reducing their invasiveness. This phenomenon may be related to the different impact of the short and prolonged activation of the AKT kinase and to the repression of STAT3 signalling. Bioinformatics analyses confirmed the positive correlation of breast cancer patients' survival with AKT activation and up-regulation of CCS. Eventually, metabolomics studies demonstrate a prevalence of glycolysis over mitochondrial energetic metabolism and of lipidome changes in TNBC cells upon TRIEN treatment. CONCLUSIONS: We provide evidence of a pivotal role of copper in AKT-driven EMT activation, acting independently of HER2 in TNBC cells and via a profound change in their metabolism. Our results support the use of copper-chelators as an adjuvant therapeutic strategy for TNBC.

Vitamin D Supplementation Impacts Systemic Biomarkers of Collagen Degradation and Copper Metabolism in Patients With Keratoconus.

Purpose: To evaluate the impact of vitamin D (Vit D) supplementation on systemic biomarkers of collagen degradation, inflammation, oxidative stress, and copper metabolism in adolescent patients with keratoconus (KC). Methods: This was a prospective observational pilot study. Twenty patients (age range, 16-19 years) presenting KC and Vit D insufficiency (<30 ng/mL) were included. Vit D supplementation was prescribed by their general practitioner as per the standard of care. Patients were followed up for 12 months. At each visit, best spectacle-corrected visual acuity (BSCVA), maximal keratometry (Kmax), and thinnest corneal thickness (TCT) were evaluated. The primary outcome of the study was the proportion of patients with Kmax progression of less than 1 D throughout the 12-month follow-up time. Blood samples were collected at different time points to evaluate Vit D levels and systemic markers of collagen degradation, inflammation, oxidative stress, and copper metabolism by ELISA or RT-PCR. Results: Lower Vit D levels in the plasma were correlated with higher levels of systemic biomarkers of collagen degradation. Vit D supplementation increased the cell availability of copper. Moreover, stabilization of KC progression was found in 60% of patients (72% of eyes) after 12 months with Vit D supplementation. BSCVA, Kmax, and TCT rates remained stable during the observation period. Conclusions: Our findings support that Vit D administration could affect ocular and systemic biomarkers in KC and illuminate a possible mechanism that can be used to develop new treatment alternatives. Translational Relevance: Although KC therapy currently relies exclusively on surgical procedures, Vit D supplementation may offer a non-invasive and inexpensive alternative with minimal associated side effects.

A hollow Co3-xCuxS4 with glutathione depleting and photothermal properties for synergistic dual-enhanced chemodynamic/photothermal cancer therapy.

Chemodynamic therapy has become an emerging cancer treatment strategy, in which tumor cells are killed through toxic reactive oxygen species (ROS), especially hydroxyl radicals (˙OH) produced by the Fenton reaction. Nevertheless, low ROS generation efficiency and ROS depletion by cellular antioxidant systems are still the main obstacles in chemodynamic therapy. In the present work, we propose a dually enhanced chemodynamic therapy obtained by inhibiting ˙OH consumption and promoting ˙OH production based on the administration of bimetallic sulfide Co3-xCuxS4 nanoparticles functionalized by polyethylene glycol. These bimetallic nanoparticles display glutathione depleting and photothermal properties. The nanoparticles are gradually degraded in a tumor microenvironment, resulting in Co2+ and Cu2+ release. The released Co2+ triggers a Fenton-like reaction that turns endogenous hydrogen peroxide into highly toxic ˙OH. In the cellular environment, Cu2+ ions are reduced to Cu+ by endogenous GSH, which decreases the intracellular antioxidant capacity and additionally up-regulates ˙OH production via the Cu+-induced Fenton-like reaction. Moreover, under near-infrared light irradiation, the bimetallic nanoparticles display a photothermal conversion efficacy of 46.7%, which not only improves chemodynamic therapy via boosting a Fenton-like reaction but results in photothermal therapy through hyperthermia. Both in vitro cancer cell killing and in vivo tumor ablation experiments show that the bimetallic nanoparticles display outstanding therapeutic efficacy and negligible systemic toxicity, indicating their anticancer potential.

Supplementation With Vitamin E, Zinc, Selenium, and Copper Re-Establishes T-Cell Function and Improves Motor Recovery in a Rat Model of Spinal Cord Injury.

Spinal cord injury (SCI) causes a dysfunction of sympathetic nervous system innervation that affects the immune system, leading to immunosuppression syndrome (ISS) and contributing to patient degeneration and increased risk of several infections. A possible therapeutic strategy that could avoid further patient deterioration is the supplementation with Vitamin E or trace elements, such as Zinc, Selenium, and Copper, which individually promotes T-cell differentiation and proliferative responses. For this reason, the aim of the present study was to evaluate whether Vitamin E, Zinc, Selenium, and Copper supplementation preserves the number of T-lymphocytes and improves their proliferative function after traumatic SCI. Sprague-Dawley female rats were subjected to moderate SCI and then randomly allocated into three groups: (1) SCI + supplements; (2) SCI + vehicle (olive oil and phosphate-buffered saline); and (3) sham-operated rats. In all rats, the intervention was initiated 15 min after SCI and then administered daily until the end of study. Locomotor recovery was assessed at 7 and 15 days after SCI. At 15 days after supplementation, the quantification of the number of T-cells and its proliferation function were examined. Our results showed that the SCI + supplements group presented a significant improvement in motor recovery at 7 and 15 days after SCI. In addition, this group showed a better T-cell number and proliferation rate than that observed in the group with SCI + vehicle. Our findings suggest that Vitamin E, Zinc, Selenium, and Copper supplementation could be part of a therapy for patients suffering from acute SCI, helping to preserve T-cell function, avoiding complications, and promoting a better motor recovery. All procedures were approved by the Animal Bioethics and Welfare Committee (Approval No. 201870; CSNBTBIBAJ 090812960).

Flexible CuS-embedded human serum albumin hollow nanocapsules with peroxidase-like activity for synergistic sonodynamic and photothermal cancer therapy.

Nanoparticle flexibility is an important parameter in determining cell uptake and tumor accumulation, thus modulating therapeutic efficiency in cancer treatment. Herein, we successfully prepared CuS-embedded human serum albumin hollow nanocapsules (denoted CuS/HSA) by a hard-core-assisted layer-by-layer coating approach. This approach afforded CuS/HSA hollow nanocapsules with controllable shell thickness, tunable flexibility, uniform size (272.9 nm), a large hollow cavity, peroxidase-like activity, excellent photothermal conversion ability, and a high tetra-(4-aminophenyl) porphyrin (TAPP) loading capacity (27.3 wt%). The peroxidase-like activity of the CuS nanoparticles enabled them to overcome tumor hypoxia and augment the sonodynamic therapeutic (SDT) effects and photothermal conversion ability for photothermal therapy (PTT). In vitro experiments showed that the CuS/HSA-TAPP hollow nanocapsules efficiently induced cancer cell apoptosis under US irradiation and cancer cell ablation under laser irradiation, thus facilitating synergistic SDT and PTT. Importantly, the flexibility of the CuS/HSA hollow nanocapsules resulted in significantly enhanced cellular internalization and a longer mean residence time (131.3 h) than their solid counterparts (21.0 h). In a breast tumor model, the flexible CuS/HSA hollow nanocapsules exhibited high tumor accumulation of up to 27.1%. In vivo experiments demonstrated that the flexible CuS/HSA-TAPP hollow nanocapsules effectively eliminated breast tumors via the synergistic effect of SDT and PTT.

Effects of Sodium Chlorophyllin Copper on APO-1 Expression in Bone Marrow Mesenchymal Stem Cells of Rats with Aplastic Anaemia.

Background: Aplastic anaemia (AA) is a highly prevalent blood disorder in the East and Southeast Asian countries, and a proportion of the patients is poorly treated with immunosuppressive agents. This study is aimed at exploring the effects of sodium copper chlorophyllin (SCC) on rats with AA and at providing the theoretical basis for the treatment of AA using traditional Chinese medicine. Methods: A rat model of AA was induced by combining 5-fluorouracil with busulfan, and different groups were treated with 25 mg/kg cyclosporin A (CsA) and low-, medium-, and high-dose SCC (25-, 50-, and 100-mg/kg; L-, M-, and H-SCC, respectively). A comparative analysis of peripheral blood counts, T-cell subsets, cytokine levels, bone marrow pathology, and APO-1 expression in mesenchymal stem cells in each group was conducted. Results: SCC can increase the platelet count and haemoglobin concentration in the peripheral blood of AA rats, whereas bone marrow biopsies revealed that the number of nucleated cells and megakaryocytes of SCC-treated rats increased compared with the model group. This was particularly evident in the H-SCC group. As regards the correction of immune function, unlike CsA, which reduced the absolute CD8+ T-cell count, SCC corrected the imbalanced CD4/CD8 ratio by increasing the absolute CD4+ T-cell count, whereas SCC increased the number of regulatory T-cells and reduced the level of interferon-γ in AA rats. When comparing the expression of APO-1 in the MSCs, results of the reverse-transcriptase polymerase chain reaction and Western blot analysis showed that SCC can increase the expression of APO-1 both at the mRNA and protein levels. Conclusion: We found that SCC can improve haematopoietic function and regress immune disorders in AA rats, which enhanced the expression of APO-1 in bone marrow MSCs. This may be one of the mechanisms of SCC in treating AA.

Copper and zinc deficiency in an alcoholic patient: a case report of a therapeutic dilemma.

Copper deficiency often manifests with anemia and ataxia. The risk factors associated with the deficiency include gastrointestinal surgery, excessive zinc supplementation, and malabsorptive conditions. Little is known about the relationship between copper deficiency and alcohol consumption. Here we report a case of copper deficiency in a patient with alcohol use disorder who also had zinc deficiency, thereby posing a therapeutic dilemma because copper and zinc are competitively absorbed into the small intestine. Early recognition of copper deficiency is essential when treating zinc deficiency in such patients.

Facile synthesis of bromelain copper nanoparticles to improve the primordial therapeutic potential of copper against acute myocardial infarction in diabetic rats.

Our current investigation comprises the synthesis and pharmacological impact of bromelain copper nanoparticles (BrCuNP) against diabetes mellitus (DM) and associated ischemia/reperfusion (I/R) - induced myocardial infarction. Bromelain is a proteolytic enzyme obtained from Ananas comosus L. Merr., which has blood platelet aggregation inhibiting and arterial thrombolytic potential. Moreover, copper is well-known to facilitate glucose metabolism and strengthen cardiac muscle and antioxidant activity; although, chronic or long-term exposure to high doses of copper may lead to copperiedus. To restrict these potential hazards, we synthesized herbal nano-formulation which convincingly indicated the improved primordial therapeutic potential of copper by reformulating the treatment carrier with bromelain, resulting in facile synthesis of BrCuNP. DM was induced by administration of double cycle repetitive dose of low dose streptozotocin (20 mg/kg, i.p.) in high-fat diet- fed animals. DM and associated myocardial I/R injury were estimated by increased serum levels of total cholesterol, low-density lipoprotein, very low-density lipoprotein, lactate dehydrogenase, creatine kinase myocardial band, cardiac troponin, thiobarbituric acid reactive substances, tumor necrosis factor α, interleukin 6, and reduced serum level of high-density lipoprotein and nitrite/nitrate concentration. However, treatment with BrCuNP ameliorates various serum biomarkers by approving cardioprotective potential against DM- and I/R-associated injury. Furthermore, upturn of histopathological changes were observed in cardiac tissue of BrCuNP-treated rats in comparison to disease models.