-
Small (Weinheim An Der Bergstrasse,... Jun 2024Nanomaterials with biomimetic catalytic abilities have attracted significant attention. However, the stereoselectivity of natural enzymes determined by their unique...
Nanomaterials with biomimetic catalytic abilities have attracted significant attention. However, the stereoselectivity of natural enzymes determined by their unique configurations is difficult to imitate. In this work, a kind of chiral CuCoS-CuS nanoflowers (L/D-Pen-NFs) is developed, using porous CuCoS nanoparticles (NPs) as stamens, CuS sheets as petals, and chiral penicillamine as surface stabilizers. Compared to the natural laccase enzyme, L/D-Pen-NFs exhibit significant advantages in catalytic efficiency, stability against harsh environments, recyclability, and convenience in construction. Most importantly, they display high enantioselectivity toward chiral neurotransmitters, which is proved by L- and D-Pen-NFs' different catalytic efficiencies toward chiral enantiomers. L-Pen-NFs are more efficient in catalyzing the oxidation of L-epinephrine and L-dopamine compared with D-Pen-NFs. However, their catalytic efficiency in oxidizing L-norepinephrine and L-DOPA is lower than that of D-Pen-NFs. The reason for the difference in catalytic efficiency is the distinct binding affinities between CuCoS-CuS nano-enantiomers and chiral molecules. This work can spur the development of chiral nanostructures with biomimetic functions.
Topics: Catalysis; Copper; Stereoisomerism; Nanostructures; Biomimetics; Oxidation-Reduction; Laccase
PubMed: 38196019
DOI: 10.1002/smll.202311275 -
Advanced Materials (Deerfield Beach,... Mar 2024The dense extracellular matrix (ECM) in the pancreatic cancer severely hampers the penetration of nanodrugs, which causes inferior therapeutic efficacy. To address this...
Photo-Triggered Cascade Therapy: A NIR-II AIE Luminogen Collaborating with Nitric Oxide Facilitates Efficient Collagen Depletion for Boosting Pancreatic Cancer Phototheranostics.
The dense extracellular matrix (ECM) in the pancreatic cancer severely hampers the penetration of nanodrugs, which causes inferior therapeutic efficacy. To address this issue, a multifunctional liposome, namely, Lip-DTI/NO, integrating a type-I photosensitizer DTITBT with glutathione (GSH) or heat-responsive nitric oxide (NO) donor S-nitroso-N-acetyl-D-penicillamine (SNAP) is constructed to deplete the tumor ECM, leading to enhanced drug delivery and consequently improved phototherapy. The loaded DTITBT possesses multiple functions including NIR-II fluorescence imaging, efficient superoxide radical (O ) generation and excellent photothermal conversion efficiency, making it feasible for precisely pinpointing the tumor in the phototherapy process. Responding to the intracellular overexpressed glutathione or heat produced by photothermal effect of DTITBT, NO can be released from SNAP. Upon 808 nm laser irradiation, Lip-DTI/NO could selectively induce in situ generation of peroxynitrite anion (ONOO) in tumor after cascade processes including O production, GSH or heat-triggered NO release, and rapid reaction between O and NO. The generated ONOO could activate the expression of endogenous matrix metalloproteinases which could efficiently digest collagen of tumor ECM, thus facilitating enhanced penetration and accumulation of Lip-DTI/NO in tumor. In vivo evaluation demonstrates the notable therapeutic efficacy via ONOO-potentiated synergistic photodynamic-photothermal therapies on both subcutaneous and orthotopic pancreatic cancer model.
Topics: Humans; Nitric Oxide; Phototherapy; Photochemotherapy; Neoplasms; Pancreatic Neoplasms; Collagen; Glutathione; Cell Line, Tumor; Nanoparticles
PubMed: 38157423
DOI: 10.1002/adma.202306476 -
Pharmaceutics Dec 2023(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...
(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.
PubMed: 38140060
DOI: 10.3390/pharmaceutics15122719 -
Hepatology (Baltimore, Md.) May 2024Trientine (TRI) and D-penicillamine (PEN) are used to treat copper overload in Wilson disease. Their main mode of action is thought to be through the facilitation of...
BACKGROUND AND AIMS
Trientine (TRI) and D-penicillamine (PEN) are used to treat copper overload in Wilson disease. Their main mode of action is thought to be through the facilitation of urinary copper excretion. In a recent study, TRI was noninferior to PEN despite lower 24-hour urinary copper excretion than PEN. We tested whether TRI and/or PEN also inhibit intestinal copper absorption.
APPROACH AND RESULTS
Sixteen healthy volunteers were examined with positron emission tomography (PET)/CT 1 and 15 hours after an oral Copper-64 ( 64 Cu) dose. They then received 7 days of either PEN or TRI (trientine tetrahydrochloride), after which the 64 Cu PET/CT scans were repeated. Venous blood samples were also collected. Pretreatment to posttreatment changes of the hepatic 64 Cu uptake reflect the effect of drugs on intestinal absorption. 64 Cu activity was normalized to dose and body weight and expressed as the mean standard uptake value. TRI (n=8) reduced hepatic 64 Cu activity 1 hour after 64 Cu dose from 6.17 (4.73) to 1.47 (2.97) standard uptake value, p <0.02, and after 15 hours from 14.24 (3.09) to 6.19 (3.43), p <0.02, indicating strong inhibition of intestinal 64 Cu absorption. PEN (n=8) slightly reduced hepatic standard uptake value at 15 hours, from 16.30 (5.63) to 12.17 (1.44), p <0.04.
CONCLUSIONS
In this mechanistic study, we show that TRI inhibits intestinal copper absorption, in addition to its cupriuretic effect. In contrast, PEN has modest effects on the intestinal copper absorption. This may explain why TRI and PEN are equally effective although urinary copper excretion is lower with TRI. The study questions whether the same therapeutic targets for 24-hour urinary excretion apply to both drugs.
Topics: Humans; Penicillamine; Trientine; Copper; Positron Emission Tomography Computed Tomography; Copper Radioisotopes; Hepatolenticular Degeneration; Positron-Emission Tomography
PubMed: 38088886
DOI: 10.1097/HEP.0000000000000708 -
Environmental Toxicology Mar 2024Ovarian cancer (OV) is an aggressive malignancy that poses a significant threat to the health and lives of women. Cuproptosis is a newly discovered form of programmed...
Ovarian cancer (OV) is an aggressive malignancy that poses a significant threat to the health and lives of women. Cuproptosis is a newly discovered form of programmed cell death that offers a promising therapeutic target, although its significance in cancer progression remains uncertain. In this study, we established a prognostic model of OV with six cuproptosis-related long non-coding RNAs (lncRNAs), including CTC.246B18.8, LINC00337, RP11.568N6.1, RP11.158I9.8, RP11.678G14.3 and CYP4F26P, based on the data of The Cancer Genome Atlas (TCGA). Lower risk scores were associated with favorable prognosis. In addition, a negative outcome was associated with high expression of CTC.246B18.8. According to the ESTIMATE algorithm, CTC.246B18.8 was negatively correlated with the ImmuneScore, and positively with immune checkpoints, immune cell infiltration, and tumor mutation burden (TMB). Moreover, gene set enrichment analysis (GSEA) revealed that pathways related to immunosuppression are likely activated in response to CTC-246B18.8 overexpression. Furthermore, CTC-246B18.8 expression was also associated with the sensitivity to various chemotherapy drugs. The expression patterns of the above lncRNAs were verified in ovarian tumor cell lines (SK-OV-3, COC1, and A2780) and normal ovarian epithelial cells (IOSE - 80). Six cuproptosis-related genes (CRGs), including ATP7B, MTF1, SLC31A1, DLD, ATP7A and DLAT, were differentially expressed between CTC-246B18.8 and CTC-246B18.8 patient groups, and exhibited organ-specific expression patterns pan-cancer. Small molecule drugs that target these CRGs were predicted, and potential candidates included DIAMIDE, bathocuproine disulfonate, D-penicillamine, etc. To summarize, our findings provide molecular insights into the role of cuproptosis in OV, and the signature lncRNAs and CRGs should be investigated further as immunotherapy biomarkers of OV.
Topics: Female; Humans; Ovarian Neoplasms; RNA, Long Noncoding; Cell Line, Tumor; Multiomics; Apoptosis; Copper
PubMed: 38019212
DOI: 10.1002/tox.24067 -
Mechanistic analysis of the photolytic decomposition of solid-state S-nitroso-N-acetylpenicillamine.Nitric Oxide : Biology and Chemistry Jan 2024S-Nitroso-N-acetylpenicillamine (SNAP) is among the most common nitric oxide (NO)-donor molecules and its solid-state photolytic decomposition has potential for inhaled...
S-Nitroso-N-acetylpenicillamine (SNAP) is among the most common nitric oxide (NO)-donor molecules and its solid-state photolytic decomposition has potential for inhaled nitric oxide (iNO) therapy. The photochemical NO release kinetics and mechanism were investigated by exposing solid-state SNAP to a narrow-band LED as a function of nominal wavelength and intensity of incident light. The photolytic efficiency, decomposition products, and the photolytic pathways of the SNAP were examined. The maximum light penetration depth through the solid layer of SNAP was determined by an optical microscope and found to be within 100-200 μm, depending on the wavelength of light. The photolysis of solid-state SNAP to generate NO along with the stable thiyl (RS·) radical was confirmed using Electron Spin Resonance (ESR) spectroscopy. The fate of the RS· radical in the solid phase was studied both in the presence and absence of O using NMR, IR, ESR, and UPLC-MS. The changes in the morphology of SNAP due to its photolysis were examined using PXRD and SEM. The stable thiyl radical formed from the photolysis of solid SNAP was found to be reactive with another adjacent thiyl radical to form a disulfide (RSSR) or with oxygen to form various sulfonyl and sulfonyl peroxyl radicals {RS(O)O·, x = 0 to 7}. However, the thiyl radical did not recombine with NO to reform the SNAP. From the PXRD data, it was found that the SNAP loses its crystallinity by generating the NO after photolysis. The initial release of NO during photolysis was increased with increased intensity of light, whereas the maximum light penetration depth was unaffected by light intensity. The knowledge gained about the photochemical reactions of SNAP may provide important insight in designing portable photoinduced NO-releasing devices for iNO therapy.
Topics: S-Nitroso-N-Acetylpenicillamine; Nitric Oxide; Photolysis; Chromatography, Liquid; Tandem Mass Spectrometry; Nitric Oxide Donors; Oxygen
PubMed: 37979933
DOI: 10.1016/j.niox.2023.11.001 -
Therapie 2024Drug-induced kidney diseases represent a wide range of diseases that are responsible for a significant proportion of all acute kidney injuries and chronic kidney... (Review)
Review
Drug-induced kidney diseases represent a wide range of diseases that are responsible for a significant proportion of all acute kidney injuries and chronic kidney diseases. In the present review, we focused on drug-induced glomerular diseases, more precisely podocytopathies - minimal change diseases (MCD), focal segmental glomerulosclerosis (FSGS) - and membranous nephropathies (MN), from a physiological and a pharmacological point of view. The glomerular filtration barrier is composed of podocytes that form foot processes tightly connected and directly in contact with the basal membrane and surrounding capillaries. The common clinical feature of these diseases is represented by the loss of the ability of the filtration barrier to retain large proteins, leading to massive proteinuria and nephrotic syndrome. Drugs such as non-steroidal anti-inflammatory drugs (NSAIDs), D-penicillamine, tiopronin, trace elements, bisphosphonate, and interferons have been historically associated with the occurrence of MCD, FSGS, and MN. In the last ten years, the development of new anti-cancer agents, including tyrosine kinase inhibitors and immune checkpoint inhibitors, and research into their renal adverse effects highlighted these issues and have improved our comprehension of these diseases.
Topics: Humans; Glomerulosclerosis, Focal Segmental; Kidney Glomerulus; Kidney Diseases; Podocytes; Nephrosis, Lipoid
PubMed: 37973491
DOI: 10.1016/j.therap.2023.10.010 -
World Journal of Hepatology Oct 2023Wilson disease is an autosomal recessive disorder affecting the ATP7B gene located on chromosome 13q. This leads to copper deposition in various organs, most importantly... (Review)
Review
Wilson disease is an autosomal recessive disorder affecting the ATP7B gene located on chromosome 13q. This leads to copper deposition in various organs, most importantly in the liver and brain. The genetic mutations are vast, well reported in the West but poorly documented in developing countries. Hence the diagnosis is made with a constellation of clinico-laboratory parameters which have significant overlap with other liver diseases and often pose a significant dilemma for clinicians. Diagnostic scoring systems are not fool-proof. The availability and affordability of chelators in developing countries impact the drug compliance of patients. While D-penicillamine is a potent drug, its side effects lead to drug discontinuation. Trientine is cost-prohibitive in developing countries. There is no single test to assess the adequacy of chelation. Exchangeable urinary copper is an essential upcoming diagnostic and prognostic tool. In the presence of cirrhosis, hypersplenism clouds the assessment of myelosuppression of drugs. Similarly, it may be difficult to distinguish disease tubulopathy from drug-induced glomerulonephritis. Neurological worsening due to chelators may appear similar to disease progression. Presentation as fulminant hepatic failure requires rapid workup. There is a limited window of opportunity to salvage these patients with the help of plasmapheresis and other liver-assisted devices. This review addresses the challenges and clinical dilemmas faced at beside in developing countries.
PubMed: 37970614
DOI: 10.4254/wjh.v15.i10.1109 -
Molecular Neurobiology May 2024Neurodegenerative diseases (NDDs) have been increasing in incidence in recent years and are now widespread worldwide. Neuronal death is defined as the progressive loss... (Review)
Review
Neurodegenerative diseases (NDDs) have been increasing in incidence in recent years and are now widespread worldwide. Neuronal death is defined as the progressive loss of neuronal structure or function which is closely associated with NDDs and represents the intrinsic features of such disorders. Amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer's, Parkinson's, and Huntington's diseases (AD, PD, and HD, respectively) are considered neurodegenerative diseases that affect a large number of people worldwide. Despite the testing of various drugs, there is currently no available therapy that can remedy or effectively slow the progression of these diseases. Nanomedicine has the potential to revolutionize drug delivery for the management of NDDs. The use of nanoparticles (NPs) has recently been developed to improve drug delivery efficiency and is currently subjected to extensive studies. Nanoengineered particles, known as nanodrugs, can cross the blood-brain barrier while also being less invasive compared to the most treatment strategies in use. Polymeric, magnetic, carbonic, and inorganic NPs are examples of NPs that have been developed to improve drug delivery efficiency. Primary research studies using NPs to cure AD are promising, but thorough research is needed to introduce these approaches to clinical use. In the present review, we discussed the role of metal-based NPs, polymeric nanogels, nanocarrier systems such as liposomes, solid lipid NPs, polymeric NPs, exosomes, quantum dots, dendrimers, polymersomes, carbon nanotubes, and nanofibers and surfactant-based systems for the therapy of neurodegenerative diseases. In addition, we highlighted nanoformulations such as N-butyl cyanoacrylate, poly(butyl cyanoacrylate), D-penicillamine, citrate-coated peptide, magnetic iron oxide, chitosan (CS), lipoprotein, ceria, silica, metallic nanoparticles, cholinesterase inhibitors, an acetylcholinesterase inhibitors, metal chelators, anti-amyloid, protein, and peptide-loaded NPs for the treatment of AD.
Topics: Humans; Alzheimer Disease; Animals; Drug Carriers; Drug Delivery Systems; Blood-Brain Barrier; Nanoparticles; Multifunctional Nanoparticles
PubMed: 37966683
DOI: 10.1007/s12035-023-03730-z -
Journal of Nephrology Mar 2024Cystinuria is a rare genetic kidney stone disease, with no cure. Current treatments involve lowering urinary cystine levels and increasing cystine solubility. This... (Review)
Review
BACKGROUND
Cystinuria is a rare genetic kidney stone disease, with no cure. Current treatments involve lowering urinary cystine levels and increasing cystine solubility. This systematic review evaluates the available literature regarding non-surgical interventions for cystinuria.
METHODS
Key electronic databases were searched for studies that described the clinical management of cystinuria with high diuresis, alkalinizing agents and thiol-based drugs that were published between 2000 and 2022. Observational studies were included if they contained clinical investigation with at least one previous or current episode of cystine stones, urine cystine levels > 250 mg/L and patients being managed with urinary dilution, alkalinizing agents or other pharmacological agents. All included studies were assessed for study design, patient characteristics and outcomes. A qualitative and critical analysis was performed whereby study quality was assessed using Methodological Index for Non-Randomized Studies (MINORS). Two authors performed the quality assessment and excluded the studies with a low MINORS score.
RESULTS
Fourteen studies met the review inclusion and quality criteria. Of the fourteen studies, two reported treatment using alkalinizing agents, six reported treatment using thiol-based drugs, and six reported combination treatment using alkalinizing agents and thiol-based drugs. These studies indicated that first-line therapies, including high fluid intake and urinary alkalinization, increased urine volume to > 3 L/day and urinary pH > 7.0, and were associated with reduced urinary cystine levels and cystine stone formation. Second-line therapy with cystine-binding thiol drugs, such as tiopronin and D-penicillamine, reduced urinary cystine levels, cystine crystal volume and increased cystine solubility, resulting in decreased cystine stone formation and stone recurrence rate. Further, combined intervention with alkalinizing agents and thiol-based drugs synergistically reduced stone recurrence.
CONCLUSION
Cystinuria treatment may require a combined approach of high diuresis, alkalinization and pharmacological interventions with regular monitoring of urinary pH, cystine levels, cystine crystal volume and solubility. However, poor adherence to treatment is relatively frequent, hence the pressing urgency for improved therapies and treatments.
Topics: Cystinuria; Humans; Cystine; Sulfhydryl Compounds; Treatment Outcome; Diuresis
PubMed: 37957454
DOI: 10.1007/s40620-023-01795-6