ABSTRACT
This study presents a novel approach for the fabrication of a Co,Ni/MoS2-derived nanohybrid material using wheat straw extract. The facile synthesis method involves a sol-gel process, followed by calcination, showcasing the potential of agricultural waste as a sustainable reducing and chelating reagent. The as-prepared nanohybrid has been characterized using different techniques to analyse its physicochemical properties. X-ray diffraction analysis confirmed the successful synthesis of the nanohybrid material, identifying the presence of NiMoO4, CoSO4 and Mo17O47 as its components. Fourier-transform infrared spectroscopy differentiated the functional groups present in the wheat straw biomass and those in the nanohybrid material, highlighting the formation of metal-oxide and sulphide bonds. Scanning electron microscopy revealed a heterogeneous morphology with agglomerated structures and a grain size of around 70 nm in the nanohybrid. Energy-dispersive X-ray spectroscopy analysis shows the composition of elements with weight percentages of (Mo) 9.17%, (S) 6.21%, (Co) 12.48%, (Ni) 12.18% and (O) 50.46% contributing to its composition. Electrochemical analysis performed through cyclic voltammetry showcased the exceptional performance of the nanohybrid material as compared with MoS2, suggesting its possible applications for designing biosensors and related technologies. Thus, the research study presented herein underscores the efficient utilization of natural resources for the development of functional nanomaterials with promising applications in various fields. This study paves a way for manufacturing innovation along with advancement of novel synthesis method for sustainable nanomaterial for future technological developments.
Subject(s)
Cobalt , Disulfides , Molybdenum , Nickel , Triticum , Triticum/chemistry , Molybdenum/chemistry , Disulfides/chemistry , Nickel/chemistry , Cobalt/chemistry , Plant Extracts/chemistry , Particle Size , Surface PropertiesABSTRACT
The objective of the present study was to develop a novel molybdenum disulfide/iron oxide/gold nanorods (MoS2/Fe3O4/GNR) nanocomposite (MFG) with different concentrations of AgNO3 solution (MFG1, MFG2, and MFG3) for topical doxorubicin (DOX) drug delivery. Then, these nanocomposites were synthesized and characterized by Fourier transform infrared (FTIR), Transmission electron microscopy (TEM), Dynamic light scattering (DLS), and Ultraviolet-visible (UV-Vis) spectroscopies to confirm their structural and optical properties. Cytotoxicity of samples on Hela cell was determined using MTT assay. Results indicated that nanocomposites possess little cytotoxicity without NIR laser irradiation. Also, the relative viabilities of Hela cells decreased when the concentration of AgNO3 solution increased in this nanocomposite. Using NIR irradiation, the relative viabilities of Hela cells decreased when the concentration of samples increased. Acridine orange/propidium iodide (PI) staining, flow cytometry were recruited to evaluate the effect of these nanocomposites on apoptosis of Hela cells. Finally, results revealed when DOX loading increased in nanocomposite, then cell viability was decreased in it. Therefore, these properties make MFG3 nanocomposite a good candidate for photothermal therapy and drug loading.
Subject(s)
Cell Survival , Disulfides , Doxorubicin , Gold , Molybdenum , Nanocomposites , Humans , Molybdenum/chemistry , Molybdenum/pharmacology , HeLa Cells , Nanocomposites/chemistry , Disulfides/chemistry , Gold/chemistry , Cell Survival/drug effects , Doxorubicin/pharmacology , Doxorubicin/chemistry , Nanotubes/chemistry , Apoptosis/drug effects , Photothermal Therapy/methods , Neoplasms/drug therapy , Neoplasms/therapy , Spectroscopy, Fourier Transform Infrared , Phototherapy/methods , Ferric Compounds/chemistryABSTRACT
BACKGROUND: The importance of multi-target simultaneous detection lies in its ability to significantly boost detection efficiency, making it invaluable for rapid and cost-effective testing. Photoelectrochemical (PEC) sensors have emerged as promising candidates for detecting harmful substances and biomarkers, attributable to their unparalleled sensitivity, minimal background signal, cost-effectiveness, equipment simplicity, and outstanding repeatability. However, designing an effective multi-target detection strategy remains a challenging task in the PEC sensing field. Consequently, there is a pressing need to address the development of PEC sensors capable of simultaneously detecting multiple targets. RESULTS: CdIn2S4/V-MoS2 heterojunctions were successfully prepared via a hydrothermal method. These heterojunctions exhibited a high photocurrent intensity, representing a 1.53-fold enhancement compared to CdIn2S4 alone. Next, we designed a multi-channel aptasensing chip using ITO as the substrate. Three working electrodes were created via laser etching and subsequently modified with CdIn2S4/V-MoS2 heterojunctions. Thiolated aptamers were then self-assembled onto the CdIn2S4/V-MoS2 heterojunctions via covalent bonds, serving as recognition tool. By empolying the CdIn2S4/V-MoS2 heterojunctions as the sensing platform and aptamers as recognition tool, we successfully developed a disposable aptasensing chip for the simultaneous PEC detection of three typical mycotoxins (aflatoxin B1 (AFB1), ochratoxin A (OTA), and zearalenone (ZEN)). This aptasensing chip exhibited wide detection range for AFB1 (0.05-50 ng/mL), OTA (0.05-500 ng/mL), and ZEN (0.1-250 ng/mL). Furthermore, it demonstrated ultra-low detection limits of 0.017 ng/mL for AFB1, 0.016 ng/mL for OTA, and 0.033 ng/mL for ZEN. SIGNIFICANCE AND NOVELTY: The aptasensing chip stands out for its cost-effectiveness, simplicity of fabrication, and multi-channel capabilities. The versatility and practicality enable it to serve as a powerful platform for designing multi-channel PEC aptasensors. With its ability to detect multiple targets with high sensitivity and specificity, the aptasensing chip holds immense potential for applications across diverse fields, such as environmental monitoring, clinical diagnostics, and food safety monitoring, where multi-target detection is crucial.
Subject(s)
Aptamers, Nucleotide , Disulfides , Electrochemical Techniques , Molybdenum , Semiconductors , Molybdenum/chemistry , Electrochemical Techniques/instrumentation , Electrochemical Techniques/methods , Aptamers, Nucleotide/chemistry , Disulfides/chemistry , Limit of Detection , Nanostructures/chemistry , Photochemical Processes , Mycotoxins/analysis , Biosensing Techniques , Cadmium Compounds/chemistry , Ochratoxins/analysisABSTRACT
Disulfide bonds, covalently formed by sulfur atoms in cysteine residues, play a crucial role in protein folding and structure stability. Considering their significance, artificial disulfide bonds are often introduced to enhance protein thermostability. Although an increasing number of tools can assist with this task, significant amounts of time and resources are often wasted owing to inadequate consideration. To enhance the accuracy and efficiency of designing disulfide bonds for protein thermostability improvement, we initially collected disulfide bond and protein thermostability data from extensive literature sources. Thereafter, we extracted various sequence- and structure-based features and constructed machine-learning models to predict whether disulfide bonds can improve protein thermostability. Among all models, the neighborhood context model based on the Adaboost-DT algorithm performed the best, yielding "area under the receiver operating characteristic curve" and accuracy scores of 0.773 and 0.714, respectively. Furthermore, we also found AlphaFold2 to exhibit high superiority in predicting disulfide bonds, and to some extent, the coevolutionary relationship between residue pairs potentially guided artificial disulfide bond design. Moreover, several mutants of imine reductase 89 (IR89) with artificially designed thermostable disulfide bonds were experimentally proven to be considerably efficient for substrate catalysis. The SS-bond data have been integrated into an online server, namely, ThermoLink, available at guolab.mpu.edu.mo/thermoLink.
Subject(s)
Disulfides , Machine Learning , Disulfides/chemistry , Databases, Protein , Enzyme Stability , Models, Molecular , Protein FoldingABSTRACT
Numerous enveloped viruses, such as coronaviruses, influenza, and respiratory syncytial virus (RSV), utilize class I fusion proteins for cell entry. During this process, the proteins transition from a prefusion to a postfusion state, undergoing substantial and irreversible conformational changes. The prefusion conformation has repeatedly shown significant potential in vaccine development. However, the instability of this state poses challenges for its practical application in vaccines. While non-native disulfides have been effective in maintaining the prefusion structure, identifying stabilizing disulfide bonds remains an intricate task. Here, we present a general computational approach to systematically identify prefusion-stabilizing disulfides. Our method assesses the geometric constraints of disulfide bonds and introduces a ranking system to estimate their potential in stabilizing the prefusion conformation. We hypothesized that disulfides restricting the initial stages of the conformational switch could offer higher stability to the prefusion state than those preventing unfolding at a later stage. The implementation of our algorithm on the RSV F protein led to the discovery of prefusion-stabilizing disulfides that supported our hypothesis. Furthermore, the evaluation of our top design as a vaccine candidate in a cotton rat model demonstrated robust protection against RSV infection, highlighting the potential of our approach for vaccine development.
Subject(s)
Disulfides , Viral Fusion Proteins , Disulfides/chemistry , Animals , Viral Fusion Proteins/immunology , Viral Fusion Proteins/chemistry , Humans , Respiratory Syncytial Virus Infections/immunology , Respiratory Syncytial Virus Infections/prevention & control , Respiratory Syncytial Virus Infections/virology , Protein Stability , Computer-Aided Design , Protein Conformation , Respiratory Syncytial Viruses/immunology , Respiratory Syncytial Virus Vaccines/immunology , Rats , Models, MolecularABSTRACT
Garlic is a vegetable with numerous pro-health properties, showing high antioxidant capacity, and cytotoxicity for various malignant cells. The inhibition of cell proliferation by garlic is mainly attributed to the organosulfur compounds (OSCs), but it is far from obvious which constituents of garlic indeed participate in the antioxidant and cytotoxic action of garlic extracts. This study aimed to obtain insight into this question by examining the antioxidant activity and cytotoxicity of six OSCs and five phenolics present in garlic. Three common assays of antioxidant activity were employed (ABTSâ decolorization, DPPHâ decolorization, and FRAP). Cytotoxicity of both classes of compounds to PEO1 and SKOV-3 ovarian cancer cells, and MRC-5 fibroblasts was compared. Negligible antioxidant activities of the studied OSCs (alliin, allicin, S-allyl-D-cysteine, allyl sulfide, diallyl disulfide, and diallyl trisulfide) were observed, excluding the possibility of any significant contribution of these compounds to the total antioxidant capacity (TAC) of garlic extracts estimated by the commonly used reductive assays. Comparable cytotoxic activities of OSCs and phenolics (caffeic, p-coumaric, ferulic, gallic acids, and quercetin) indicate that both classes of compounds may contribute to the cytotoxic action of garlic.
Subject(s)
Allyl Compounds , Antioxidants , Disulfides , Garlic , Phenols , Plant Extracts , Sulfides , Sulfinic Acids , Garlic/chemistry , Humans , Antioxidants/pharmacology , Antioxidants/chemistry , Phenols/pharmacology , Phenols/chemistry , Disulfides/pharmacology , Disulfides/chemistry , Cell Line, Tumor , Plant Extracts/pharmacology , Plant Extracts/chemistry , Sulfinic Acids/pharmacology , Sulfinic Acids/chemistry , Sulfides/pharmacology , Sulfides/chemistry , Allyl Compounds/pharmacology , Allyl Compounds/chemistry , Sulfur Compounds/pharmacology , Sulfur Compounds/chemistry , Cysteine/analogs & derivatives , Cysteine/chemistry , Cysteine/pharmacology , Cell Survival/drug effects , Cell Proliferation/drug effects , Fibroblasts/drug effects , Fibroblasts/metabolismABSTRACT
BACKGROUND: The unique size, physical and chemical properties, and ultra-high stability of nanozymes have attracted extensive attentions in sensing, but improvement of catalytic activity of the nanozymes is still an urgent issue. Given the ultra-high simulated enzyme activity of metal nanoparticles and the advantage of multi-enzyme catalysis, an Au-decorated MoS2 nanosheets (MoS2/Au NS) integrating the double peroxidase-like (POD) activity is developed. RESULTS: By optimizing and adjusting the density of AuNPs, as well as its morphology and other parameters, a monodisperse and high-density distribution of AuNPs on MoS2 nanosheets was obtained, which can greatly improve the POD-like activity of MoS2/Au NS. Nafion solution was applied to assist the modification of MoS2/Au NS on the electrode surface so as to improved its stability. An electrochemical H2O2 detection platform was constructed by modifying MoS2/Au NS nanozyme on the SPCE using the conductive Nafion solution. And the negatively charged sulfonic acid group can eliminate negatively charged electroactive substances to improve the specificity. Then ascorbic acid was used to stimulate tumor cells to produce H2O2 as therapeutic model, an ultrasensitive chronocoulometry detection for H2O2 in cell lysate was established. The logarithmically of ΔQ and the logarithmically of H2O2 concentration showed a good linear relationship between 1 µM and 500 mM, with a LOD value of 0.3 µM. SIGNIFICANCE: The developed H2O2 sensor has excellent stability, reproducibility (RSD = 2.3 %, n = 6) and selectivity, realized the quantitative detection of H2O2 in cell lysate. Compared with commercial fluorescence detection kits for H2O2 in cell lysate, it is worth mentioning that the electrochemical H2O2 sensor developed in this study is simpler and faster, with higher sensitivity and lower cost. This provides a potential substitute for disease diagnosis and treatment evaluation based on accurate detection of H2O2.
Subject(s)
Antineoplastic Agents , Disulfides , Electrochemical Techniques , Gold , Hydrogen Peroxide , Metal Nanoparticles , Molybdenum , Gold/chemistry , Molybdenum/chemistry , Hydrogen Peroxide/analysis , Hydrogen Peroxide/chemistry , Disulfides/chemistry , Metal Nanoparticles/chemistry , Electrochemical Techniques/methods , Humans , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/analysis , Nanostructures/chemistry , Limit of Detection , Peroxidase/chemistry , Peroxidase/metabolism , Drug Screening Assays, AntitumorABSTRACT
Redox-responsive homodimer prodrug nanoassemblies (RHPNs) have emerged as a significant technology for overcoming chemotherapeutical limitations due to their high drug-loading capacity, low excipient-associated toxicity, and straightforward preparation method. Previous studies indicated that α-position disulfide bond bridged RHPNs exhibited rapid drug release rates but unsatisfactory assembly stability. In contrast, γ-disulfide bond bridged RHPNs showed better assembly stability but low drug release rates. Therefore, designing chemical linkages that ensure both stable assembly and rapid drug release remains challenging. To address this paradox of stable assembly and rapid drug release in RHPNs, we developed carbon-spaced double-disulfide bond (CSDD)-bridged RHPNs (CSDD-RHPNs) with two carbon-spaces. Pilot studies showed that CSDD-RHPNs with two carbon-spaces exhibited enhanced assembly stability, reduction-responsive drug release, and improved selective toxicity compared to α-/γ-position single disulfide bond bridged RHPNs. Based on these findings, CSDD-RHPNs with four and six carbon-spaces were designed to further investigate the properties of CSDD-RHPNs. These CSDD-RHPNs exhibited excellent assembly ability, safety, and prolonged circulation. Particularly, CSDD-RHPNs with two carbon-spaces displayed the best antitumor efficacy on 4T1 and B16-F10 tumor-bearing mice. CSDD chemical linkages offer novel perspectives on the rational design of RHPNs, potentially overcoming the design limitations regarding contradictory assembly ability and drug release rate.
Subject(s)
Carbon , Disulfides , Prodrugs , Disulfides/chemistry , Prodrugs/chemistry , Animals , Mice , Carbon/chemistry , Humans , Drug Liberation , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Design , Cell Line, Tumor , Nanostructures/chemistry , Dimerization , Doxorubicin/chemistry , Doxorubicin/pharmacologyABSTRACT
The issue of bacterial infectious diseases remains a significant concern worldwide, particularly due to the misuse of antibiotics, which has caused the emergence of antibiotic-resistant strains. Fortunately, the rapid development of nanomaterials has propelled significant progress in antimicrobial therapy, offering promising solutions. Among them, the utilization of nanoenzyme-based chemodynamic therapy (CDT) has become a highly hopeful approach to combating bacterial infectious diseases. Nevertheless, the application of CDT appears to be facing certain constraints for its low efficiency in the Fenton reaction at the infected site. In this study, we have successfully synthesized a versatile nanozyme, which was a composite of molybdenum sulfide (MoS2) and iron sulfide (FeS2), through the hydrothermal method. The results showed that iron/molybdenum sulfide nanozymes (Fe/Mo SNZs) with desirable peroxidase (POD) mimic activity can generate cytotoxic reactive oxygen species (ROS) by successfully triggering the Fenton reaction. The presence of MoS2 significantly accelerates the conversion of Fe2+/Fe3+ through a cocatalytic reaction that involves the participation of redox pairs of Mo4+/Mo6+, thereby enhancing the efficiency of CDT. Additionally, based on the excellent photothermal performance of Fe/Mo SNZs, a near-infrared (NIR) laser was used to induce localized temperature elevation for photothermal therapy (PTT) and enhance the POD-like nanoenzymatic activity. Notably, both in vitro and in vivo results demonstrated that Fe/Mo SNZs with good broad-spectrum antibacterial properties can help eradicate Gram-negative bacteria like Escherichia coli and Gram-positive bacteria like Staphylococcus aureus. The most exciting thing is that the synergistic PTT/CDT exhibited astonishing antibacterial ability and can achieve complete elimination of bacteria, which promoted wound healing after infection. Overall, this study presents a synergistic PTT/CDT strategy to address antibiotic resistance, providing avenues and directions for enhancing the efficacy of wound healing treatments and offering promising prospects for further clinical use in the near future.
Subject(s)
Anti-Bacterial Agents , Disulfides , Iron , Molybdenum , Sulfides , Wound Healing , Molybdenum/chemistry , Molybdenum/pharmacology , Wound Healing/drug effects , Sulfides/chemistry , Sulfides/pharmacology , Animals , Disulfides/chemistry , Disulfides/pharmacology , Iron/chemistry , Iron/pharmacology , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/chemical synthesis , Catalysis , Staphylococcus aureus/drug effects , Mice , Escherichia coli/drug effects , Hydrogen Peroxide/chemistry , Hydrogen Peroxide/pharmacology , Reactive Oxygen Species/metabolism , Nanostructures/chemistry , Phototherapy , Microbial Sensitivity Tests , Photothermal Therapy , Ferrous CompoundsABSTRACT
Thiol-disulfide interconversions are pivotal in the intricate chemistry of biological systems. They play a vital role in governing cellular redox potential and shielding against oxidative harm. These interconversions can also act as molecular switches within an expanding array of redox-regulated proteins, facilitating dynamic and responsive processes. Furthermore, metal-binding proteins often use thiols for coordination. Reverse thiol trapping is a valuable analytical tool to study the redox state of cysteines in biological systems. By selectively capturing and stabilizing free thiol species with an alkylating agent, reverse thiol trapping allows for their subsequent identification and quantification. Various methods can be employed to analyze the trapped thiol adducts, including electrophoresis-based methods, mass spectrometry, nuclear magnetic resonance spectroscopy, and chromatographic techniques. In this chapter, we will focus on describing a simple and sensitive method to sequentially block thiols in their cellular state with a cell-permeant agent (iodoacetamide), and following reduction and denaturation of the samples, trap the native disulfides with a second blocker that shifts the apparent molecular weight of the protein. The oxidation status of proteins for which suitable antibodies are available can then be analyzed by immunoblotting. We present examples of mitochondrial proteins that use cysteine thiols to coordinate metal factors such as iron-sulfur clusters, zinc, and copper.
Subject(s)
Mitochondrial Proteins , Oxidation-Reduction , Sulfhydryl Compounds , Sulfhydryl Compounds/chemistry , Sulfhydryl Compounds/metabolism , Mitochondrial Proteins/metabolism , Mitochondrial Proteins/chemistry , Humans , Iodoacetamide/chemistry , Disulfides/chemistry , Disulfides/metabolism , Metals/chemistry , Metals/metabolism , Cysteine/chemistry , Cysteine/metabolismABSTRACT
Galectins are multifunctional effectors in cellular homeostasis and dysregulation. Oxidation of human galectin-1 (Gal-1) with its six sulfhydryls produces a disulfide-bridged oxidized form that lacks normal lectin activity yet gains new glycan-independent functionality. Nevertheless, the mechanistic details as to how Gal-1 oxidation occurs remain unclear. Here, we used 15N and 13C HSQC NMR spectroscopy to gain structural insight into the CuSO4-mediated path of Gal-1 oxidation and identified a minimum two-stage conversion process. During the first phase, disulfide bridges form slowly between C16-C88 and/or C42-C66 to produce a partially oxidized, conformationally flexible intermediate that retains the ability to bind lactose. Site-directed mutagenesis of C16 to S16 impedes the onset of this overall slow process. During the second phase, increased motional dynamics of the intermediate enable the relatively distant C2 and C130 residues to form the third and final disulfide bond, leading to an unfolded state and consequent dimer dissociation. This fully oxidized end state loses the ability to bind lactose, as shown by the hemagglutination assay. Consistent with this model, we observed that the Gal-1 C2S mutant maintains intermediate-state structural features with a free sulfhydryl group at C130. Incubation with dithiothreitol reduces all disulfide bonds and allows the lectin to revert to its native state. Thus, the sequential, non-random formation of three disulfide bridges in Gal-1 in an oxidative environment acts as a molecular switch for fundamental changes to its functionality. These data inspire detailed bioactivity analysis of the structurally defined oxidized intermediate in, e.g., acute and chronic inflammation.
Subject(s)
Cysteine , Galectin 1 , Oxidation-Reduction , Galectin 1/metabolism , Galectin 1/chemistry , Galectin 1/genetics , Humans , Cysteine/metabolism , Cysteine/chemistry , Disulfides/metabolism , Disulfides/chemistry , Protein Folding , Protein Unfolding , Models, Molecular , Lactose/metabolism , Lactose/chemistry , Mutagenesis, Site-DirectedABSTRACT
This study aimed to develop a highly efficient nanocomposite composed of magnetic chitosan/molybdenum disulfide (CS/MoS2/Fe3O4) for the removal of three polycyclic aromatic hydrocarbons (PAHs)-pyrene, anthracene, and phenanthrene. Novelty was introduced through the innovative synthesis procedure and the utilization of magnetic properties for enhanced adsorption capabilities. Additionally, the greenness of chitosan as a sorbent component was emphasized, highlighting its biodegradability and low environmental impact compared to traditional sorbents. Factors influencing PAH adsorption, such as nanocomposite dosage, initial PAH concentration, pH, and contact time, were systematically investigated and optimized. The results revealed that optimal removal efficiencies were attained at an initial PAH concentration of 150 mg/L, a sorbent dose of 0.045 g, pH 6.0, and a contact time of 150 min. The pseudo-second-order kinetic model exhibited superior fitting to the experimental data, indicating an equilibrium time of approximately 150 min. Moreover, the equilibrium adsorption process followed the Freundlich isotherm model, with kf and n values exceeding 7.91 mg/g and 1.20, respectively. Remarkably, the maximum absorption capacities for phenanthrene, anthracene, and pyrene on the sorbent were determined as 217 mg/g, 204 mg/g, and 222 mg/g, respectively. These findings underscore the significant potential of the CS/MoS2/Fe3O4 nanocomposite for efficiently removing PAHs from milk and other dairy products, thereby contributing to improved food safety and public health.
Subject(s)
Chitosan , Disulfides , Milk , Molybdenum , Nanocomposites , Polycyclic Aromatic Hydrocarbons , Disulfides/chemistry , Nanocomposites/chemistry , Chitosan/chemistry , Polycyclic Aromatic Hydrocarbons/chemistry , Polycyclic Aromatic Hydrocarbons/isolation & purification , Molybdenum/chemistry , Milk/chemistry , Animals , Adsorption , Kinetics , Hydrogen-Ion ConcentrationABSTRACT
The chemical properties of disulfides are leveraged in a wide array of applications, ranging from protein-drug conjugates for cancer treatment to self-healing materials. However, disulfide reduction strategies remain severely underdeveloped despite being the key to efficiently accessing the desired targets. Specifically, no homogeneous catalyst has been reported for this reaction, and conditions that allow the use of mild and green reductants (e.g., via electrochemical reduction) are not known. Herein, we unveil a vitamin B12-catalyzed, electrochemically driven protocol for efficiently reducing disulfide bonds in various aqueous buffers over a broad pH range. This robust and simple method is suitable for disulfide reductions of substrates ranging from small molecules to large proteins. Finally, one-pot reduction and conjugation of disulfide bonds in a monoclonal antibody were demonstrated to produce antibody conjugates.
Subject(s)
Disulfides , Oxidation-Reduction , Vitamin B 12 , Disulfides/chemistry , Catalysis , Molecular Structure , Vitamin B 12/chemistry , Electrochemical Techniques , Antibodies, Monoclonal/chemistry , Hydrogen-Ion Concentration , Immunoconjugates/chemistryABSTRACT
The performance of catalytic ability of MFe2O4/MoS2 in the ozonation process was investigated in this work. The synthesized MnFe2O4/MoS2 was optimize prepared and then characterized by scanning electron microscopy, transmission electron microscopy, X-ray diffraction, X-ray photo-electron spectroscopy, and magnetic saturation strength. The results showed that when Cphenol = 200 mg/L, initial pH = 9.0, Q = 0.10 L/min, and CMnFe2O4/MoS2 = 0.10 g/L, MnFe2O4/MoS2 addition improved the degradation efficiency of phenol by 20.0%. The effects of pH, catalyst dosage, and inorganic ions on the phenol removal by the MnFe2O4/MoS2 catalytic ozonation were investigated. Five cycle experiments proved that MnFe2O4/MoS2 had good recyclability and stability. MnFe2O4/MoS2 also showed good catalytic performance in the treatment of coal chemical wastewater pesticide wastewater. The MnFe2O4 doped with MoS2 could provide abundant surface active sites for ozone and promote the stable cycle of Mn2+/Mn3+and Fe2+/Fe3+, thus generating large amounts of â¢OH and improving the degradation of phenol by ozonation. The MnFe2O4/MoS2/ozonation treatment system provides a technical reference and theoretical basis for industrial wastewater treatment.
Subject(s)
Ozone , Wastewater , Wastewater/chemistry , Ozone/chemistry , Catalysis , Ferric Compounds/chemistry , Manganese Compounds/chemistry , Waste Disposal, Fluid/methods , Water Pollutants, Chemical/chemistry , Water Purification/methods , Phenols/chemistry , Molybdenum/chemistry , Disulfides/chemistryABSTRACT
The conversion of a soluble protein into polymeric amyloid structures is a process that is poorly understood. Here, we describe a fully redox-regulated amyloid system in which cysteine oxidation of the tumor suppressor protein p16INK4a leads to rapid amyloid formation. We identify a partially-structured disulfide-bonded dimeric intermediate species that subsequently assembles into fibrils. The stable amyloid structures disassemble when the disulfide bond is reduced. p16INK4a is frequently mutated in cancers and is considered highly vulnerable to single-point mutations. We find that multiple cancer-related mutations show increased amyloid formation propensity whereas mutations stabilizing the fold prevent transition into amyloid. The complex transition into amyloids and their structural stability is therefore strictly governed by redox reactions and a single regulatory disulfide bond.
Subject(s)
Amyloid , Cyclin-Dependent Kinase Inhibitor p16 , Cysteine , Oxidation-Reduction , Amyloid/metabolism , Amyloid/chemistry , Humans , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Cyclin-Dependent Kinase Inhibitor p16/genetics , Cysteine/metabolism , Cysteine/chemistry , Disulfides/metabolism , Disulfides/chemistry , Sulfhydryl Compounds/metabolism , Sulfhydryl Compounds/chemistry , Mutation , PolymerizationABSTRACT
Insulin icodec is a once-weekly insulin analogue that has a long half-life of approximately 7 days, making it suitable for once weekly dosing. The Insulin icodec molecule was developed based on the hypothesis that lowering insulin receptor affinity and introducing a strong albumin-binding moiety would result in a long insulin half-life, provided that non-receptor-mediated clearance is diminished. Here, we report an insulin clearance mechanism, resulting in the splitting of insulin molecules into its A-chain and B-chain by a thiol-disulphide exchange reaction. Even though the substitutions in insulin icodec significantly stabilise insulin against such degradation, some free B-chain is observed in plasma samples from minipigs and people with type 2 diabetes. In summary, we identify thiol-disulphide exchange reactions to be an important insulin clearance mechanism and find that stabilising insulin icodec towards this reaction significantly contributes to its long pharmacokinetic/pharmacodynamic profile.
Subject(s)
Diabetes Mellitus, Type 2 , Disulfides , Insulin , Animals , Humans , Male , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/blood , Disulfides/chemistry , Half-Life , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/chemistry , Insulin/administration & dosage , Insulin/metabolism , Insulin/chemistry , Insulin/pharmacokinetics , Receptor, Insulin/metabolism , Sulfhydryl Compounds/chemistry , Swine , Swine, MiniatureABSTRACT
Double pH-responsive xenopeptides comprising polar ionizable succinoyl tetraethylene pentamine (Stp) motifs and lipophilic ionizable lipoamino fatty acids (LAFs) were recently found to efficiently transfect mRNA and pDNA at low doses. However, potency was often accompanied with cytotoxicity at higher doses. Insertion of bioreducible disulfide building blocks (ssbb) or non-reducible hydrophobic spacers between polar and apolar ionizable domains of LAF-Stp carriers should mitigate toxicity of xenopeptides. Carriers showed stable nucleic acid complexation and endosomal pH-dependent lytic activities, both of which were abolished after reductive cleavage of ssbb-containing carriers. For pDNA, U-shaped carriers with one Stp and two LAF units or bundle carriers with two Stps and four LAFs displayed highest potency. For mRNA, best transfection was achieved with bundle carriers with one Stp and four LAFs. Both the ssbb and hydrophobic spacer containing analogs displayed improved metabolic activity, reduced membrane damage, and improved cell growth. The ssbb carriers were most beneficial regarding living cell count and low apoptosis rates. Mechanistically, inserted spacers decelerated the transfection kinetics and altered the requirement of endosomal protonation. Overall, mRNA and pDNA carriers with improved biocompatibility have been designed, with their high potency illustrated in transfection of various cell lines including low passage number colon carcinoma cells.
Subject(s)
Disulfides , Fatty Acids , Hydrophobic and Hydrophilic Interactions , Transfection , Humans , Fatty Acids/chemistry , Disulfides/chemistry , Hydrogen-Ion Concentration , RNA, Messenger/metabolism , RNA, Messenger/genetics , DNA/chemistry , Cell Line, Tumor , Plasmids/chemistry , Plasmids/metabolism , Cell Survival/drug effects , Apoptosis/drug effectsABSTRACT
Peptide cyclization is often used to introduce conformational rigidity and to enhance the physiological stability of the peptide. This study presents a novel late-stage cyclization method for creating thioketal cyclic peptides from bis-cysteine peptides and drugs. Symmetrical cyclic ketones and acetone were found to react with bis-cysteine unprotected peptides efficiently to form thioketal linkages in trifluoroacetic acid (TFA) without any other additive. The attractive features of this method include high chemoselectivity, operational simplicity, and robustness. In addition, TFA as the reaction solvent can dissolve any unprotected peptide. As a showcase, the dimethyl thioketal versions of lanreotide and octreotide were prepared and evaluated, both of which showed much improved reductive stability and comparable activity.
Subject(s)
Disulfides , Ketones , Peptides, Cyclic , Trifluoroacetic Acid , Ketones/chemistry , Trifluoroacetic Acid/chemistry , Cyclization , Peptides, Cyclic/chemistry , Peptides, Cyclic/chemical synthesis , Molecular Structure , Disulfides/chemistry , Cysteine/chemistry , Octreotide/chemistry , Octreotide/chemical synthesis , Peptides/chemistry , Peptides/chemical synthesisABSTRACT
A small molecule disulfide unit technology platform based on dynamic thiol exchange chemistry at the cell membrane has the potential for drug delivery. However, the alteration of the CSSC dihedral angle of the disulfide unit caused by diverse substituents directly affects the effectiveness of this technology platform as well as its own chemical stability. The highly stable open-loop relaxed type disulfide unit plays a limited role in drug delivery due to its low dihedral angle. Here, we have built a novel disulfide unit starship based on the 3,4,5-trihydroxyphenyl skeleton through trigonometric bundling. The intracellular delivery results showed that the trigonometric bundling of the disulfide unit starship effectively promoted cellular uptake without any toxicity, which is far more than 100 times more active than that of equipment with a single disulfide unit in particular. Then, the significant reduction in cell uptake capacity (73-93%) using thiol erasers proves that the trigonometric bundling of the disulfide starship is an endocytosis-independent internalization mechanism via a dynamic covalent disulfide exchange mediated by thiols on the cell surface. Furthermore, analysis of the molecular dynamics simulations demonstrated that trigonometric bundling of the disulfide starship can significantly change the membrane curvature while pushing lipid molecules in multiple directions, resulting in a significant distortion in the membrane structure and excellent membrane permeation performance. In conclusion, the starship system we built fully compensates for the inefficiency deficiencies induced by poor dihedral angles.