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Bioengineering & Translational Medicine May 2023Chemodynamic therapy (CDT) is based on the production of cytotoxic reactive oxygen species, such as hydroxyl radicals (OH). Thus, CDT can be advantageous when it is...
Chemodynamic therapy (CDT) is based on the production of cytotoxic reactive oxygen species, such as hydroxyl radicals (OH). Thus, CDT can be advantageous when it is cancer-specific, in terms of efficacy and safety. Therefore, we propose NH-MIL-101(Fe), a Fe-containing metal-organic framework (MOF), as a carrier of Cu (copper)-chelating agent, d-penicillamine (d-pen; i.e., the NH-MIL-101(Fe)/d-pen), as well as a catalyst with Fe-metal clusters for Fenton reaction. NH-MIL-101(Fe)/d-pen in the form of nanoparticles was efficiently taken into cancer cells and released d-pen in a sustained manner. The released d-pen chelated Cu that is highly expressed in cancer environments and this produces extra HO, which is then decomposed by Fe in NH-MIL-101(Fe) to generate OH. Therefore, the cytotoxicity of NH-MIL-101(Fe)/d-pen was observed in cancer cells, not in normal cells. We also suggest a formulation of NH-MIL-101(Fe)/d-pen combined with NH-MIL-101(Fe) loaded with the chemotherapeutic drug, irinotecan (CPT-11; NH-MIL-101(Fe)/CPT-11). When intratumorally injected into tumor-bearing mice in vivo, this combined formulation exhibited the most prominent anticancer effects among all tested formulations, owing to the synergistic effect of CDT and chemotherapy.
PubMed: 37206221
DOI: 10.1002/btm2.10477 -
Nanomaterials (Basel, Switzerland) Apr 2023Inorganic chiral nanoparticles are attracting more and more attention due to their peculiar optical properties and potential biological applications, such as bioimaging,...
Inorganic chiral nanoparticles are attracting more and more attention due to their peculiar optical properties and potential biological applications, such as bioimaging, therapeutics, and diagnostics. Among inorganic chiral nanoparticles, gold chiral nanostructures were demonstrated to be very interesting in this context, with good physical chemical stability and also the possibility to decorate the surface, improving biomedical application as the interaction with the bio-systems. Gold (Au) nanostructures were synthesized according to a seed-mediated procedure which envisages the use of cetyltrimethylammonium bromide (CTAB) as the capping agent and L- and D-cysteine to promote chirality. Au nanostructures have been demonstrated to have opposite circular dichroism signals depending on the amino acid enantiomer used during the synthesis. Then, a procedure to decorate the Au surface with penicillamine, a drug used for the treatment of Wilson's disease, was developed. The composite material of gold nanoparticles/penicillamine was characterized using electron microscopy, and the penicillamine functionalization was monitored by means of UV-Visible, Raman, and infrared spectroscopy, highlighting the formation of the Au-S bond. Furthermore, electron circular dichroism was used to monitor the chirality of the synthesized nanostructures and it was demonstrated that both penicillamine enantiomers can be successfully bonded with both the enantiomers of the gold nanostructures without affecting gold nanoparticles' chirality. The effective modification of nanostructures' surfaces via penicillamine introduction allowed us to address the important issue of controlling chirality and surface properties in the chiral nano-system.
PubMed: 37177071
DOI: 10.3390/nano13091526 -
Annals of Medicine Dec 2023Excessive oxygen free radicals and toxic substances are generated in cerebral ischemia-reperfusion (I/R) process. Dexmedetomidine (DEX), a common anesthetic and sedative...
Excessive oxygen free radicals and toxic substances are generated in cerebral ischemia-reperfusion (I/R) process. Dexmedetomidine (DEX), a common anesthetic and sedative drug, can considerably boost glutathione (GSH), which has anti-copper influx effects. Focusing on cuproptosis, the mechanism of DEX in the I/R was revealed. Using the I/R rat model, the effects of DEX and the copper chelator D-penicillamine on cerebral infarct volume, copper levels, mitochondrial respiration and membrane potential, GSH content, and enrichment of cuproptosis functional proteins were examined. The involvement of ferredoxin 1 (FDX1) in the DEX regulatory pathway was verified by overexpressing FDX1 . DEX could significantly reduce cerebral infarction in rats, reduce copper levels, maintain mitochondrial functions, increase GSH, and reduce the content of key proteins related to cuproptosis. These aspects were replicated and revealed that FDX1 overexpression partially reversed the impacts of DEX. Together, cuproptosis occurs in the brain I/R process and DEX can enhance cell survival by blocking the primary pathway mediated by FDX1.KEY MESSAGESDexmedetomidine reduces cerebral infarction in the I/R rat models.Dexmedetomidine reduces cuproptosis in the I/R rat models.FDX1, an upstream of protein fatty acylation, mediates regulation of Dexmedetomidine.
Topics: Animals; Rats; Apoptosis; Brain Ischemia; Cerebral Infarction; Dexmedetomidine; Ferredoxins; Homeostasis; Reperfusion; Reperfusion Injury
PubMed: 37162502
DOI: 10.1080/07853890.2023.2209735 -
Biomedicine & Pharmacotherapy =... Jul 2023Recently, cuproptosis has been demonstrated to be a new non-apototic cell death mode that is characterized by copper dependence and the regulation of mitochondrial... (Review)
Review
Recently, cuproptosis has been demonstrated to be a new non-apototic cell death mode that is characterized by copper dependence and the regulation of mitochondrial respiration. Cuproptosis is distinct from known cell death modes such as apoptosis, necrosis, pyroptosis, or ferroptosis. Excessive copper induces cuproptosis by promoting protein toxic stress reactions via copper-dependent anomalous oligomerization of lipoylation proteins in the tricarboxylic acid (TCA) cycle and reducing iron-sulfur cluster protein levels. Ferredoxin1 (FDX1) promotes dihydrolipoyl transacetylase (DLAT) lipoacylation and abates iron-sulfur cluster proteins by reducing Cu to Cu, inducing cell death. Copper homeostasis depends on the copper transporter, and disturbances to this homeostasis cause cuproptosis. Recent evidence has shown that cuproptosis plays a significant role in the occurrence and development of many cardiovascular diseases, such as myocardial ischemia/reperfusion (I/R) injury, heart failure, atherosclerosis, and arrhythmias. Copper chelators, such as ammonium tetrathiomolybdate(VI) and DL-Penicillamine, may ease the above cardiovascular diseases by inhibiting the cuproptosis pathway. Oxidative phosphorylation inhibitors may inhibit cuproptosis by inhibiting protein stress response. In conclusion, cuproptosis plays an essential role in cardiovascular disease pathogenesis. Inhibition of cardiovascular cuproptosis is expected to become a potential treatment. Here, we will thoroughly review the molecular mechanisms involved in cuproptosis and its significance in cardiovascular disease.
Topics: Humans; Cardiovascular Diseases; Copper; Heart Failure; Apoptosis; Sulfur; Iron
PubMed: 37150036
DOI: 10.1016/j.biopha.2023.114830 -
Scientific Reports May 2023Hydrogen sulfide (HS) is a gaseous signaling molecule that participates in various signaling functions in health and diseases. The tetrameric cystathionine γ-lyase...
Hydrogen sulfide (HS) is a gaseous signaling molecule that participates in various signaling functions in health and diseases. The tetrameric cystathionine γ-lyase (CSE) contributes to HS biogenesis and several investigations provide evidence on the pharmacological modulation of CSE as a potential target for the treatment of a multitude of conditions. D-penicillamine (D-pen) has recently been reported to selectively impede CSE-catalyzed HS production but the molecular bases for such inhibitory effect have not been investigated. In this study, we report that D-pen follows a mixed-inhibition mechanism to inhibit both cystathionine (CST) cleavage and HS biogenesis by human CSE. To decipher the molecular mechanisms underlying such a mixed inhibition, we performed docking and molecular dynamics (MD) simulations. Interestingly, MD analysis of CST binding reveals a likely active site configuration prior to gem-diamine intermediate formation, particularly H-bond formation between the amino group of the substrate and the O3' of PLP. Similar analyses realized with both CST and D-pen identified three potent interfacial ligand-binding sites for D-pen and offered a rational for D-pen effect. Thus, inhibitor binding not only induces the creation of an entirely new interacting network at the vicinity of the interface between enzyme subunits, but it also exerts long range effects by propagating to the active site. Overall, our study paves the way for the design of new allosteric interfacial inhibitory compounds that will specifically modulate HS biogenesis by cystathionine γ-lyase.
Topics: Humans; Hydrogen Sulfide; Cystathionine gamma-Lyase; Signal Transduction; Cystathionine; Computer Simulation
PubMed: 37142727
DOI: 10.1038/s41598-023-34405-3 -
Frontiers in Immunology 2023The presence of antiphospholipid antibodies (aPLs) plays a pivotal role in the pathogenesis of antiphospholipid antibody syndrome (APS). This study aimed to examine the...
BACKGROUND
The presence of antiphospholipid antibodies (aPLs) plays a pivotal role in the pathogenesis of antiphospholipid antibody syndrome (APS). This study aimed to examine the diagnostic value of a set of non-criteria aPLs and their relevance with APS-related criteria and extra-criteria manifestations.
METHODS
From a prospectively constructed database, consecutive APS patients consisting of 114 primary APS (PAPS group), 54 with APS secondary to SLE (SAPS group), 9 seronegative APS (SNAPS), as well as 209 patients with systemic lupus erythematosus (SLE) and 88 healthy controls were included in this study. Levels of criteria aPLs, baseline information, and APS-related criteria and extra-criteria features were extracted from the database. Serum levels of non-criteria aPLs including aPC IgG/IgM, aPI IgG/IgM, aPE IgG/IgM/IgA, aPG IgG/IgM/IgA, anti-phosphatidic acid (aPA) IgG/IgM, aSM IgG/IgM, and aPS/PT IgG/IgM were analyzed with AESKULISA® ELISA Test Kits.
RESULTS
The addition of aPC IgG/M, aPI IgG/M, aPE IgG/M/A, aSM IgG/M, and aPA IgG/M to aCL or aβ2GPI IgG/M could significantly increase diagnostic sensitivity and accuracy. A significant difference between PAPS or SAPS and HC was presented in all non-criteria aPLs except for aSM IgM and aPG IgA. Eight out of nine SNAPS patients were positive for at least 1 aPL. Pregnancy morbidity was associated with aSM IgM (r = 0.22) and aSM IgG (r = 0.15). Pre-eclampsia or premature birth was associated with aSM IgG (r = 0.16), aPI IgG (r = 0.22), aPC IgG (r = 0.16), and aPG IgG (r = 0.18). Stroke was associated with aPI IgG (r = 0.2). The clinical association was also observed in DVT with aPS/PT IgG (r = 0.17). Valve lesion was positively associated with aSM IgM (Fisher test p = 0.039), APS nephropathy was associated with aPC IgG (OR 3.797), and livedo reticularis was associated with aPE IgM (OR 15.391).
CONCLUSION
Additional detection of non-criteria aPLs including aPC IgG/M, aPE IgG/M/A, aPI IgG/M, aSM IgG/M, and aPA IgG/M could assist in APS diagnosis. The positivity of certain aPLs was statistically associated with both criteria and extra-criteria APS clinical manifestations.
Topics: Female; Humans; Pregnancy; Antibodies, Antiphospholipid; Antiphospholipid Syndrome; East Asian People; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Lupus Erythematosus, Systemic; Penicillamine; Prevalence
PubMed: 37122726
DOI: 10.3389/fimmu.2023.1107510 -
Drug Discovery Today Jul 2023This report discusses potential therapies for treating human coronaviruses (HCoVs) and their economic impact. Specifically, we explore therapeutics that can support the... (Review)
Review
This report discusses potential therapies for treating human coronaviruses (HCoVs) and their economic impact. Specifically, we explore therapeutics that can support the body's immune response, including immunoglobulin (Ig)A, IgG and T-cell responses, to inhibit the viral replication cycle and improve respiratory function. We hypothesize that carbon quantum dots conjugated with S-nitroso-N-acetylpenicillamine (SNAP) could be a synergistic alternative cure for treating respiratory injuries caused by HCoV infections. To achieve this, we propose developing aerosol sprays containing SNAP moieties that release nitric oxide and are conjugated onto promising nanostructured materials. These sprays could combat HCoVs by inhibiting viral replication and improving respiratory function. Furthermore, they could potentially provide other benefits, such as providing novel possibilities for nasal vaccines in the future.
Topics: Humans; S-Nitroso-N-Acetylpenicillamine; Nitric Oxide; Virus Replication
PubMed: 37119964
DOI: 10.1016/j.drudis.2023.103601 -
Environmental Science & Technology May 2023The chemical and biological factors controlling microbial formation of methylmercury (MeHg) are widely studied separately, but the combined effects of these factors are...
The chemical and biological factors controlling microbial formation of methylmercury (MeHg) are widely studied separately, but the combined effects of these factors are largely unknown. We examined how the chemical speciation of divalent, inorganic mercury (Hg(II)), as controlled by low-molecular-mass thiols, and cell physiology govern MeHg formation by . We compared MeHg formation with and without addition of exogenous cysteine (Cys) to experimental assays with varying nutrient and bacterial metabolite concentrations. Cysteine additions initially (0-2 h) enhanced MeHg formation by two mechanisms: (i) altering the Hg(II) partitioning from the cellular to the dissolved phase and/or (ii) shifting the chemical speciation of dissolved Hg(II) in favor of the Hg(Cys) complex. Nutrient additions increased MeHg formation by enhancing cell metabolism. These two effects were, however, not additive since cysteine was largely metabolized to penicillamine (PEN) over time at a rate that increased with nutrient addition. These processes shifted the speciation of dissolved Hg(II) from complexes with relatively high availability, Hg(Cys), to complexes with lower availability, Hg(PEN), for methylation. This thiol conversion by the cells thereby contributed to stalled MeHg formation after 2-6 h Hg(II) exposure. Overall, our results showed a complex influence of thiol metabolism on microbial MeHg formation and suggest that the conversion of cysteine to penicillamine may partly suppress MeHg formation in cysteine-rich environments like natural biofilms.
Topics: Methylmercury Compounds; Sulfhydryl Compounds; Cysteine; Mercury; Geobacter; Cell Physiological Phenomena; Water Pollutants, Chemical
PubMed: 37098211
DOI: 10.1021/acs.est.3c00226 -
PloS One 2023We have previously reported that L-arginine, a nitric oxide synthase substrate, inhibits the basolateral 10-pS Cl- channel through the cGMP/PKG signaling pathway in the...
We have previously reported that L-arginine, a nitric oxide synthase substrate, inhibits the basolateral 10-pS Cl- channel through the cGMP/PKG signaling pathway in the thick ascending limb (TAL). As a NO releasing agent, the effect of S-nitroso-N-acetyl-penicillamine (SNAP) on the channel activity was examined in thick ascending limb of C57BL/6 mice in the present study. SNAP inhibited the basolateral 10-pS Cl- channel in a dose-dependent manner with an IC50 value of 6.6 μM. The inhibitory effect of SNAP was abolished not only by NO scavenger (carboxy-PTIO) but also by blockers of soluble guanylate cyclase (ODQ or LY-83583), indicating that the cGMP-dependent signaling pathway is involved. Moreover, the inhibitory effect of SNAP on the channel was strongly attenuated by a protein kinase G (PKG)-specific inhibitor, KT-5823, but not by the PDE2 inhibitor, BAY-60-7550. We concluded that SNAP inhibited the basolateral 10-pS Cl- channels in the TAL through a cGMP/PKG signaling pathway. As the 10-pS Cl- channel is important for regulation of NaCl absorption along the nephron, these data suggest that SNAP might be served as a regulator to prevent high-salt absorption related diseases, such as hypertension.
Topics: Mice; Animals; S-Nitroso-N-Acetylpenicillamine; Nitric Oxide Donors; Nitric Oxide; Mice, Inbred C57BL; Signal Transduction; Cyclic GMP; Guanylate Cyclase
PubMed: 37083928
DOI: 10.1371/journal.pone.0284707 -
Inorganic Chemistry May 2023The As binding of two NTA-based tripodal pseudopeptides, possessing three cysteine (ligand ) or d-penicillamine residues (ligand ) as potential coordinating groups for...
The As binding of two NTA-based tripodal pseudopeptides, possessing three cysteine (ligand ) or d-penicillamine residues (ligand ) as potential coordinating groups for soft semimetals or metal ions, was studied by experimental (UV, CD, NMR, and ESI-MS) and theoretical (DFT) methods. All of the experimental data, obtained with the variation of the As:ligand concentration ratios or pH values in some instances, evidence the exclusive formation of species with an AsS-type coordination mode. The UV-monitored titration of the ligands with arsenous acid at pH = 7.0 provided an absorbance data set that allowed for the determination of apparent stability constants of the forming species. The obtained stabilities (log' = 5.26 (As) and log' = 3.04 (As)) reflect high affinities, especially for the sterically less restricted cysteine derivative. DFT calculated structures correlate well with the spectroscopic results and, in line with the H NMR data, indicate a preference for the all- conformers resembling the As environment at the semimetal binding sites in various metalloproteins.
Topics: Arsenic; Binding Sites; Cysteine; Ligands; Metalloids; Peptides; Proteins; Sulfhydryl Compounds
PubMed: 37071818
DOI: 10.1021/acs.inorgchem.3c00563