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1.
Biomacromolecules ; 25(2): 1191-1204, 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38178792

RESUMO

This study focuses on designing hybrid theranostic nanosystems, utilizing gadolinium-doped carbon nanodots decorated with bioreducible amphoteric polyamidoamines (PAAs). The objective is to synergize the exceptional theranostic properties of gadolinium-doped carbon nanodots (CDs) with the siRNA complexation capabilities of PAAs. Linear copolymeric polyamidoamines, based on N,N'-bis(acryloyl)cystamine, arginine, and agmatine, were synthesized, resulting in three distinct amphoteric copolymers. Notably, sulfur bridges within the PAA repeating units confer pronounced susceptibility to glutathione-mediated degradation─a key attribute in the tumor microenvironment. This pathway enables controlled and stimuli-responsive siRNA release, theoretically providing precise spatiotemporal control over therapeutic interventions. The selected PAA, conjugated with CDs using the redox-sensitive spacer cystamine, formed the CDs-Cys-PAA conjugate with superior siRNA complexing capacity. Stable against polyanion exchange, the CDs-Cys-PAA/siRNA complex released siRNA in the presence of GSH. In vitro studies assessed cytocompatibility, internalization, and gene silencing efficacy on HeLa, MCF-7, and 16HBE cell lines.


Assuntos
Carbono , Poliaminas , Medicina de Precisão , Humanos , RNA Interferente Pequeno/genética , Cistamina , Gadolínio , Polímeros
2.
Biomacromolecules ; 25(2): 715-728, 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38271957

RESUMO

A gelled Pickering emulsion system was fabricated by first stabilizing linseed oil droplets in water with dialdehyde cellulose nanocrystals (DACNCs) and then cross-linking with cystamine. Cross-linking of the DACNCs was shown to occur by a reaction between the amine groups on cystamine and the aldehyde groups on the CNCs, causing gelation of the nanocellulose suspension. Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy were used to characterize the cystamine-cross-linked CNCs (cysCNCs), demonstrating their presence. Transmission electron microscopy images evidenced that cross-linking between cysCNCs took place. This cross-linking was utilized in a linseed oil-in-water Pickering emulsion system, creating a novel gelled Pickering emulsion system. The rheological properties of both DACNC suspensions and nanocellulose-stabilized Pickering emulsions were monitored during the cross-linking reaction. Dynamic light scattering and confocal laser scanning microscopy (CLSM) of the Pickering emulsion before gelling imaged CNC-stabilized oil droplets along with isolated CNC rods and CNC clusters, which had not been adsorbed to the oil droplet surfaces. Atomic force microscopy imaging of the air-dried gelled Pickering emulsion also demonstrated the presence of free CNCs alongside the oil droplets and the cross-linked CNC network directly at the oil-water interface on the oil droplet surfaces. Finally, these gelled Pickering emulsions were mixed with poly(vinyl alcohol) solutions and fabricated into self-healing composite coating systems. These self-healing composite coatings were then scratched and viewed under both an optical microscope and a scanning electron microscope before and after self-healing. The linseed oil was demonstrated to leak into the scratches, healing the gap automatically and giving a practical approach for a variety of potential applications.


Assuntos
Cistamina , Nanopartículas , Emulsões/química , Óleo de Semente do Linho , Celulose/química , Nanopartículas/química , Água/química
3.
Nano Lett ; 24(5): 1717-1728, 2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38270376

RESUMO

Surgery is the primary method to treat malignant melanoma; however, the residual microtumors that cannot be resected completely often trigger tumor recurrence, causing tumor-related mortality following melanoma resection. Herein, we developed a feasible strategy based on the combinational chemoimmunotherapy by cross-linking carboxymethyl chitosan (CMCS)-originated polymetformin (PolyMetCMCS) with cystamine to prepare stimuli-responsive nanogel (PMNG) owing to the disulfide bond in cystamine that can be cleaved by the massive glutathione (GSH) in tumor sites. Then, chemotherapeutic agent doxorubicin (DOX) was loaded in PMNG, which was followed by a hyaluronic acid coating to improve the overall biocompatibility and targeting ability of the prepared nanogel (D@HPMNG). Notably, PMNG effectively reshaped the tumor immune microenvironment by reprogramming tumor-associated macrophage phenotypes and recruiting intratumoral CD8+ T cells owing to the inherited immunomodulatory capability of metformin. Consequently, D@HPMNG treatment remarkably suppressed melanoma growth and inhibited its recurrence after surgical resection, proposing a promising solution for overcoming lethal melanoma recurrence.


Assuntos
Melanoma , Polietilenoglicóis , Polietilenoimina , Humanos , Nanogéis , Macrófagos Associados a Tumor , Cistamina , Linfócitos T CD8-Positivos , Doxorrubicina , Glutationa/química , Microambiente Tumoral , Linhagem Celular Tumoral
4.
Molecules ; 28(24)2023 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-38138632

RESUMO

(1) Background: Radioprotective agents have garnered considerable interest due to their prospective applications in radiotherapy, public health medicine, and situations of large-scale accidental radiation exposure or impending radiological emergencies. Cystamine, an organic diamino-disulfide compound, is recognized for its radiation-protective and antioxidant properties. This study aims to utilize the aqueous ferrous sulfate (Fricke) dosimeter to measure the free-radical scavenging capabilities of cystamine during irradiation by fast carbon ions. This analysis spans an energy range from 6 to 500 MeV per nucleon, which correlates with "linear energy transfer" (LET) values ranging from approximately 248 keV/µm down to 9.3 keV/µm. (2) Methods: Monte Carlo track chemistry calculations were used to simulate the radiation-induced chemistry of aerated Fricke-cystamine solutions across a broad spectrum of cystamine concentrations, ranging from 10-6 to 1 M. (3) Results: In irradiated Fricke solutions containing cystamine, cystamine is observed to hinder the oxidation of Fe2+ ions, an effect triggered by oxidizing agents from the radiolysis of acidic water, resulting in reduced Fe3+ ion production. Our simulations, conducted both with and without accounting for the multiple ionization of water, confirm cystamine's ability to capture free radicals, highlighting its strong antioxidant properties. Aligning with prior research, our simulations also indicate that the protective and antioxidant efficiency of cystamine diminishes with increasing LET of the radiation. This result can be attributed to the changes in the geometry of the track structures when transitioning from lower to higher LETs. (4) Conclusions: If we can apply these fundamental research findings to biological systems at a physiological pH, the use of cystamine alongside carbon-ion hadrontherapy could present a promising approach to further improve the therapeutic ratio in cancer treatments.


Assuntos
Cistamina , Transferência Linear de Energia , Cistamina/farmacologia , Antioxidantes , Dosímetros de Radiação , Íons , Núcleons , Água/química , Carbono
5.
Sci Adv ; 9(35): eadi3602, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37647403

RESUMO

CRISPR-Cas9 has been explored as a therapeutic agent for down-regulating target genes; the controlled delivery of Cas9 ribonucleoprotein (RNP) is essential for therapeutic efficacy and remains a challenge. Here, we report cascade dynamic assembly/disassembly of DNA nanoframework (NF) that enables the controlled delivery of Cas9 RNP. NF was prepared with acrylamide-modified DNA that initiated cascade hybridization chain reaction (HCR). Through an HCR, single-guide RNA was incorporated to NF; simultaneously, the internal space of NF was expanded, facilitating the loading of Cas9 protein. NF was designed with hydrophilic acylamino and hydrophobic isopropyl, allowing dynamic swelling and aggregation. The responsive release of Cas9 RNP was realized by introducing disulfide bond-containing N,N-bis(acryloyl)cystamine that was specifically in response to glutathione of cancer cells, triggering the complete disassembly of NF. In vitro and in vivo investigations demonstrated the high gene editing efficiency in cancer cells, the hypotoxicity in normal cells, and notable antitumor efficacy in a breast cancer mouse model.


Assuntos
Sistemas CRISPR-Cas , DNA , Animais , Camundongos , DNA/genética , Acrilamida , Proteína 9 Associada à CRISPR/genética , Cistamina , Ribonucleoproteínas
6.
Life Sci ; 321: 121564, 2023 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-36931499

RESUMO

AIMS: Transglutaminase (TG) inhibitors represent promising therapeutic interventions in cardiac fibrosis and related dysfunctions. However, it remains unknown how TG inhibition, TG2 in particular, affects the signaling systems that drive pathological fibrosis. This study aimed to examine the effect TG inhibition by cystamine on the progression of isoproterenol (ISO)-induced cardiac fibrosis and dysfunction in rats. MATERIALS AND METHODS: Cardiac fibrosis was established by intraperitoneal injection of ISO to rats (ISO group), followed by 6 weeks of cystamine injection (ISO + Cys group). The control groups were administered normal saline alone or with cystamine. Hemodynamics, lipid profile, liver enzymes, urea, and creatinine were assessed in conjunction with heart failure markers (serum NT-proANP and cTnI). Left ventricular (LV) and atrial (LA) fibrosis, total collagen content, and mRNA expression of profibrotic markers including TG2 were quantified by Masson's trichrome staining, LC-MS/MS and quantitative PCR, respectively. KEY FINDINGS: Cystamine administration to ISO rats significantly decreased diastolic and mean arterial pressures, total cholesterol, triglycerides, LDL, liver enzymes, urea, and creatinine levels, while increasing HDL. NT-proANP and cTnI serum levels remained unchanged. In LV tissues, significant reductions in ISO-induced fibrosis and elevated total collagen content were achieved after cystamine treatment, together with a reduction in TG2 concentration. Reduced mRNA expression of several profibrotic genes (COL1A1, FN1, MMP-2, CTGF, periostin, CX43) was also evidenced in LV tissues of ISO rats upon cystamine administration, whereas TGF-ß1 expression was depressed in LA tissues. Cystamine decreased TG2 mRNA expression in the LV of control rats, while LV expression of TG2 was relatively low in ISO rats irrespective of cystamine treatment. SIGNIFICANCE: TG2 inhibition by cystamine in vivo exerted cardioprotective effects against ISO-induced cardiac fibrosis in rats decreasing the LV abundance of several profibrotic markers and the content of TG2 and collagen, suggesting that TG2 pharmacological inhibition could be beneficial to alleviate cardiac fibrosis.


Assuntos
Insuficiência Cardíaca , Proteína 2 Glutamina gama-Glutamiltransferase , Ratos , Animais , Cistamina/farmacologia , Cistamina/uso terapêutico , Isoproterenol/toxicidade , Creatinina , Cromatografia Líquida , Espectrometria de Massas em Tandem , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/tratamento farmacológico , Fibrose , Transglutaminases/genética , Colágeno/metabolismo , Ureia
7.
Int J Mol Sci ; 24(2)2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36674717

RESUMO

Host-directed therapies are emerging as a promising tool in the curing of difficult-to-treat infections, such as those caused by drug-resistant bacteria. In this study, we aim to test the potential activity of the FDA- and EMA-approved drugs cysteamine and cystamine against Mycobacterium abscessus. In human macrophages (differentiated THP-1 cells), these drugs restricted M. abscessus growth similar to that achieved by amikacin. Here, we use the human ex vivo granuloma-like structures (GLS) model of infection with the M. abscessus rough (MAB-R) and smooth (MAB-S) variants to study the activity of new therapies against M. abscessus. We demonstrate that cysteamine and cystamine show a decrease in the number of total GLSs per well in the MAB-S and MAB-R infected human peripheral blood mononuclear cells (PBMCs). Furthermore, combined administration of cysteamine or cystamine with amikacin resulted in enhanced activity against the two M. abscessus morpho variants compared to treatment with amikacin only. Treatment with cysteamine and cystamine was more effective in reducing GLS size and bacterial load during MAB-S infection compared with MAB-R infection. Moreover, treatment with these two drugs drastically quenched the exuberant proinflammatory response triggered by the MAB-R variant. These findings showing the activity of cysteamine and cystamine against the R and S M. abscessus morphotypes support the use of these drugs as novel host-directed therapies against M. abscessus infections.


Assuntos
Infecções por Mycobacterium não Tuberculosas , Mycobacterium abscessus , Humanos , Amicacina/farmacologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Cisteamina/farmacologia , Cisteamina/uso terapêutico , Cistamina/farmacologia , Cistamina/uso terapêutico , Leucócitos Mononucleares , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/microbiologia , Testes de Sensibilidade Microbiana
8.
Autophagy ; 19(3): 839-857, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-35913916

RESUMO

Glioblastoma multiforme (GBM) is the most common brain malignancy insensitive to radiotherapy (RT). Although macroautophagy/autophagy was reported to be a fundamental factor prolonging the survival of tumors under radiotherapeutic stress, the autophagic biomarkers coordinated to radioresistance of GBM are still lacking in clinical practice. Here we established radioresistant GBM cells and identified their protein profiles using tandem mass tag (TMT) quantitative proteomic analysis. It was found that SDC1 and TGM2 proteins were overexpressed in radioresistant GBM cells and tissues and they contributed to the poor prognosis of RT. Knocking down SDC1 and TGM2 inhibited the fusion of autophagosomes with lysosomes and thus enhanced the radiosensitivity of GBM cells. After irradiation, TGM2 bound with SDC1 and transported it from the cell membrane to lysosomes, and then bound to LC3 through its two LC3-interacting regions (LIRs), coordinating the encounter between autophagosomes and lysosomes, which should be a prerequisite for lysosomal EPG5 to recognize LC3 and subsequently stabilize the STX17-SNAP29-VAMP8 QabcR SNARE complex assembly. Moreover, when combined with RT, cystamine dihydrochloride (a TGM2 inhibitor) extended the lifespan of GBM-bearing mice. Overall, our findings demonstrated the EPG5 tethering mode with SDC1 and TGM2 during the fusion of autophagosomes with lysosomes, providing new insights into the molecular mechanism and therapeutic target underlying radioresistant GBM.Abbreviations: BafA1: bafilomycin A1; CQ: chloroquine; Cys-D: cystamine dihydrochloride; EPG5: ectopic P-granules 5 autophagy tethering factor; GBM: glioblastoma multiforme; GFP: green fluorescent protein; LAMP2: lysosomal associated membrane protein 2; LIRs: LC3-interacting regions; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NC: negative control; RFP: red fluorescent protein; RT: radiotherapy; SDC1: syndecan 1; SNAP29: synaptosome associated protein 29; SQSTM1/p62: sequestosome 1; STX17: syntaxin 17; TGM2: transglutaminase 2; TMT: tandem mass tag; VAMP8: vesicle associated membrane protein 8; WT: wild type.


Assuntos
Autofagossomos , Glioblastoma , Camundongos , Animais , Autofagossomos/metabolismo , Autofagia , Glioblastoma/metabolismo , Cistamina/metabolismo , Proteômica , Lisossomos/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Tolerância a Radiação , Fusão de Membrana , Proteínas Relacionadas à Autofagia/metabolismo , Proteínas de Transporte Vesicular/metabolismo
9.
Pestic Biochem Physiol ; 188: 105287, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36464340

RESUMO

The application of fungicide mixture is one of the most important measures to extend the service life of highly selective fungicides. Pyraclostrobin (PYR), which has been extensively used to control plant diseases by inhibiting mitochondrial respiration of pathogenic fungi, is at a high risk of resistance development. In this study, the potential of PYR alone or in combination with cystamine, an inhibitor of microbial transglutaminase, to suppress Fusarium graminearum was tested in vitro and in vivo. A synergistic effect of PYR/CYS mixture was observed both in vitro and when applied to etiolated wheat coleoptile. The control effect of PYR/CYS mixture on F. graminearum was better than that of PYR alone, which was reflected by the increased protection effect. The discrepancies of membrane permeability and the redox-physiological state were observed between PYR and PYR/CYS treatments, suggesting that an increased PYR availability in F. graminearum mycelia could be related with the observed synergistic action. Moreover, a synergistic profile was observed between PYR and CYS in regard of massive autophagosomes in mycelia, indicating that enhanced autophagy could be involved in the mode of action of PYR/CYS mixture. The differential content of mitochondrial metabolites between PYR and PYR/CYS treatments also provided evidence for CYS contribution to the fungicidal action of PYR/CYS mixture. The results provide insight into the synergistic mechanism of action of PYR/CYS mixture and an effective way to enhance the efficiency of PYR to combat F. graminearum.


Assuntos
Cistamina , Fungicidas Industriais , Autofagia , Fungicidas Industriais/farmacologia , Permeabilidade
10.
ACS Appl Mater Interfaces ; 14(37): 41726-41741, 2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36089750

RESUMO

The on-demand replacement of multifunctional hydrogel wound dressings helps to avoid bacterial colonization, and the on-demand painless peeling of tissue adhesive hydrogels on the wound site remains a major challenge to be solved. In this work, we design and develop a series of multifunctional dynamic Schiff base network hydrogels composed of cystamine-modified hyaluronic acid, benzaldehyde-functionalized poly(ethylene glycol)-co-poly(glycerol sebacate), and polydopamine@polypyrrole nanocomposite (PDA@PPy) with mild on-demand removability to enhance drug-resistant bacteria-infected wound healing. These hydrogels exhibited ideal injectable and self-healing properties, excellent tissue adhesion, in vivo hemostasis, good antioxidation, and conductivity. PDA@PPy inspired by melanin endows hydrogels with excellent antioxidant capacity, UV-blocking ability, and photothermal anti-infection ability. Based on the dynamic oxidation-reduction response of disulfide bonds inspired by the dissociation of the tertiary spatial structure transformation of poly-polypeptide chains, these hydrogels can achieve rapid painless on-demand removal under mild conditions by adding dithiothreitol. These multifunctional hydrogels significantly promoted collagen deposition and angiogenesis in the MRSA-infected full-thickness skin repair experiment. All the results showed that these multifunctional hydrogels with painless on-demand removal property showed great potential in clinical treatment of infected wounds.


Assuntos
Polímeros , Adesivos Teciduais , Antibacterianos/química , Antibacterianos/farmacologia , Antioxidantes/química , Bactérias , Bandagens , Benzaldeídos , Colágeno , Cistamina , Decanoatos , Dissulfetos , Ditiotreitol , Glicerol/análogos & derivados , Humanos , Ácido Hialurônico , Hidrogéis/química , Hidrogéis/farmacologia , Melaninas , Polietilenoglicóis , Polímeros/farmacologia , Pirróis , Bases de Schiff , Aderências Teciduais , Raios Ultravioleta , Cicatrização
11.
Molecules ; 27(18)2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36144713

RESUMO

The use of smart nanocarriers that can modulate therapeutic release aided by biological cues can prevent undesirable cytotoxicity caused by the premature release of cytotoxic drugs during nanocarrier circulation. In this report, degradable nanocarriers based on pH/reduction dual-responsive nanogels were synthesized to encapsulate doxorubicin hydrochloride (DOX) and specifically boost the release of DOX in conditions characteristic of the cancer microenvironment. Nanogels containing anionic monomer 2-carboxyethyl acrylate (CEA) and N,N'-bis(acryloyl)cystamine (CBA) as a degradable crosslinker have been successfully synthesized via photoinitiated free radical polymerization. The loading process was conducted after polymerization by taking advantage of the electrostatic interaction between the negatively charged nanogels and the positively charged DOX. In this case, a high drug loading capacity (DLC) of up to 27.89% was achieved. The entrapment of DOX into a nanogel network could prevent DOX from aggregating in biological media at DOX concentrations up to ~160 µg/mL. Anionic nanogels had an average hydrodynamic diameter (dH) of around 90 nm with a negative zeta (ζ) potential of around -25 mV, making them suitable for targeting cancer tissue via the enhanced permeation effect. DOX-loaded nanogels formed a stable dispersion in different biological media, including serum-enriched cell media. In the presence of glutathione (GSH) and reduced pH, drug release was enhanced, which proves dual responsivity. An in vitro study using the HCT 116 colon cancer cell line demonstrated the enhanced cytotoxic effect of the NG-CBA/DOX-1 nanogel compared to free DOX. Taken together, pH/reduction dual-responsive nanogels show promise as drug delivery systems for anticancer therapy.


Assuntos
Antineoplásicos , Cistamina , Antígeno Carcinoembrionário/metabolismo , Doxorrubicina/farmacologia , Portadores de Fármacos/metabolismo , Liberação Controlada de Fármacos , Glutationa/metabolismo , Concentração de Íons de Hidrogênio , Nanogéis , Polietilenoglicóis , Polietilenoimina
12.
Drug Deliv ; 29(1): 2705-2712, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35980107

RESUMO

Prostate cancer (PCa) is the most common malignant tumor in men. Chemotherapy with docetaxel (DTX) and novel hormonal agents such as enzalutamide (EZL) and abiraterone are the preferred first-line therapeutic regimens. Prostate-specific membrane antigen (PSMA) is overexpressed on the surface of PCa cells. This study aimed to prepare a PSMA targeted (Glutamate-Urea-Lysine, GUL ligand modified), glutathione (GSH)-sensitive (Cystamine, SS), DTX and EZL co-loaded nanoparticles (GUL-SS DTX/EZL-NPs) to treat PCa. Polyethylene glycol (PEG) was conjugated with oleic acid (OA) using a GSH-sensitive ligand: cystamine (PEG-SS-OA). GUL was covalently coupled to PEG-SS-OA to achieve GUL-PEG-SS-OA. GUL-PEG-SS-OA was used to prepare GUL-SS DTX/EZL-NPs. To evaluate the in vitro and in vivo efficiency of the system, human prostate cancer cell lines and PCa cells bearing mice were applied. Single drug-loaded nanoparticle and free drugs systems were utilized for the comparison of the anticancer ability. GUL-SS DTX/EZL-NPs showed a size of 143.7 ± 4.1 nm, with a PDI of 0.162 ± 0.037 and a zeta potential of +29.1 ± 2.4 mV. GUL-SS DTX/EZL-NPs showed high cancer cell uptake of about 70%, as well as higher cell growth inhibition efficiency (a maximum 79% of cells were inhibited after treatment) than single drug-loaded NPs and free drugs. GUL-SS DTX/EZL-NPs showed the most prominent tumor inhibition ability and less systemic toxicity. The novel GUL-SS DTX/EZL-NPs could be used as a promising system for PCa therapy.


Assuntos
Antineoplásicos , Nanopartículas , Neoplasias da Próstata , Animais , Benzamidas , Linhagem Celular Tumoral , Cistamina/uso terapêutico , Docetaxel , Glutationa , Humanos , Ligantes , Masculino , Camundongos , Nitrilas , Feniltioidantoína , Polietilenoglicóis/uso terapêutico , Próstata , Neoplasias da Próstata/tratamento farmacológico
13.
Biochim Biophys Acta Gen Subj ; 1866(12): 130225, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35988704

RESUMO

The disulfide-containing molecule cystamine and the thiosulfonate thiotaurine are of interest as therapeutics. Both are precursors of taurine, but the chemistry of their metabolism is not clear. The rates at which these molecules are metabolized is also unknown. The chemistry and rate constants have been determined for a process in which cystamine is converted in four reactions to thiotaurine. Cystamine is oxidized by diamine oxidase with a specificity constant comparable to other diamine substrates. The rapid hydrogen peroxide-mediated oxidation of cystaldimine yields reactive glyoxal and thiocysteamine, which quickly performs transsulfuration with hypotaurine. Thiotaurine reacts spontaneously with hydrogen peroxide to form taurine and sulfite, but it is 15-fold less reactive than hypotaurine as an antioxidant. An estimation of biological rates of reaction indicates that cystamine is likely to be oxidized by diamine oxidase in vivo, but its metabolic products will be diverted to molecules other than thiotaurine.


Assuntos
Amina Oxidase (contendo Cobre) , Cistamina , Peróxido de Hidrogênio , Taurina/metabolismo
14.
Mol Cell Biol ; 42(6): e0052221, 2022 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-35499331

RESUMO

Ferroptosis is a form of regulated cell death resulting predominantly from catastrophic accumulation of lipid reactive oxygen species (ROS). While the antioxidant systems that counter ferroptosis have been well characterized, the mechanism underlying ferroptosis-associated accumulation of lipid ROS remains unclear. In this study, we demonstrated that protein disulfide isomerase (PDI) is a novel mediator of ferroptosis, which is responsible for the accumulation of lipid ROS and ultimately ferroptosis in MDA-MB-231 human breast cancer cells. Treatment with erastin led to a significant increase in inducible nitric oxide synthase (iNOS)-mediated nitric oxide production, which contributes to the accumulation of the death-inducing cellular lipid ROS. Small interfering RNA (siRNA)-mediated PDI knockdown or pharmacological inhibition of PDI's isomerase activity with cystamine strongly suppressed iNOS dimerization and its catalytic activation, subsequently prevented lipid ROS accumulation, and conferred strong protection against erastin-induced ferroptosis. Remarkably, PDI knockdown in MDA-MB-231 cells also largely abrogated the protective effect of cystamine against erastin-induced ferroptotic cell death. Together, these experimental observations demonstrate a noncanonical role of PDI in ferroptosis, which may serve as a potential therapeutic target for ferroptosis-related diseases.


Assuntos
Neoplasias da Mama , Ferroptose , Neoplasias da Mama/genética , Cistamina , Feminino , Humanos , Lipídeos , Piperazinas , Isomerases de Dissulfetos de Proteínas/genética , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio/metabolismo
15.
Am J Physiol Heart Circ Physiol ; 322(2): H167-H180, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34890280

RESUMO

Consumption of diets high in fat, sugar, and salt (Western diet, WD) is associated with accelerated arterial stiffening, a major independent risk factor for cardiovascular disease (CVD). Women with obesity are more prone to develop arterial stiffening leading to more frequent and severe CVD compared with men. As tissue transglutaminase (TG2) has been implicated in vascular stiffening, our goal herein was to determine the efficacy of cystamine, a nonspecific TG2 inhibitor, at reducing vascular stiffness in female mice chronically fed a WD. Three experimental groups of female mice were created. One was fed regular chow diet (CD) for 43 wk starting at 4 wk of age. The second was fed a WD for the same 43 wk, whereas a third cohort was fed WD, but also received cystamine (216 mg/kg/day) in the drinking water during the last 8 wk on the diet (WD + C). All vascular stiffness parameters assessed, including aortic pulse wave velocity and the incremental modulus of elasticity of isolated femoral and mesenteric arteries, were significantly increased in WD- versus CD-fed mice, and reduced in WD + C versus WD-fed mice. These changes coincided with respectively augmented and diminished vascular wall collagen and F-actin content, with no associated effect in blood pressure. In cultured human vascular smooth muscle cells, cystamine reduced TG2 activity, F-actin:G-actin ratio, collagen compaction capacity, and cellular stiffness. We conclude that cystamine treatment represents an effective approach to reduce vascular stiffness in female mice in the setting of WD consumption, likely because of its TG2 inhibitory capacity.NEW & NOTEWORTHY This study evaluates the novel role of transglutaminase 2 (TG2) inhibition to directly treat vascular stiffness. Our data demonstrate that cystamine, a nonspecific TG2 inhibitor, improves vascular stiffness induced by a diet rich in fat, fructose, and salt. This research suggests that TG2 inhibition might bear therapeutic potential to reduce the disproportionate burden of cardiovascular disease in females in conditions of chronic overnutrition.


Assuntos
Cistamina/farmacologia , Dieta Ocidental/efeitos adversos , Inibidores Enzimáticos/farmacologia , Proteína 2 Glutamina gama-Glutamiltransferase/antagonistas & inibidores , Rigidez Vascular/efeitos dos fármacos , Actinas/metabolismo , Animais , Aorta/metabolismo , Aorta/fisiologia , Células Cultivadas , Colágeno/metabolismo , Elasticidade , Feminino , Humanos , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/fisiologia , Análise de Onda de Pulso
16.
J Mater Chem B ; 9(37): 7734-7740, 2021 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-34586149

RESUMO

Superparamagnetic iron oxide nanoparticles with high magnetization strength and good biological safety have been widely used as magnetic resonance imaging (MRI) contrast agents for tumors. However, the accuracy of tumor diagnosis is still low due to the lack of tumor targeting and the interference signals from normal tissues. Endogenous substances in tumor (such as high levels of GSH and pH) stimuli-responsive contrast agents could offer higher sensitivity for tumor diagnosis. Herein, based on the characteristic of overexpression of GSH in tumors, we propose an ultra-small Fe3O4 assembly as an endogenous GSH responsive MRI contrast agent. The ultra-small superparamagnetic Fe3O4 are bonded to the crosslinker cystamine to synthesize Fe3O4 nanoclusters, which exhibit a T2 imaging effect. When the contrast agent reaches the tumor tissue, the disulfide bond in cystamine is induced by GSH to break, the Fe3O4 nanoclusters are disassembled into ultra-small Fe3O4 nanoparticles, and the relaxation signal changes from T2 to T1, which is helpful for accurate diagnosis of tumors. In vivo experiments have shown that Fe3O4 nanoclusters can rapidly respond to overexpressed GSH in tumor sites for T2/T1 switchable imaging. This work not only designed an endogenous GSH responsive platform through simple synthesis methods, but also improved the accuracy of tumor diagnosis through the transformation of T2/T1 MRI signals.


Assuntos
Meios de Contraste/química , Óxido Ferroso-Férrico/química , Glutationa/química , Imageamento por Ressonância Magnética/métodos , Neoplasias/diagnóstico , Animais , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cistamina/química , Feminino , Glutationa/metabolismo , Nanopartículas de Magnetita/química , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/diagnóstico por imagem
17.
Int J Biol Macromol ; 185: 592-603, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34216661

RESUMO

This paper presents a new thermal sensitive hydrogel system based on cystamine-functionalised sodium alginate-g-pluronic F127 (ACP). The introduction of cystamine to the alginate backbone not only creates a covalent bond with pluronic F127 but also provides intrinsic anti-bacterial activity for the resultant hydrogel. The amount of water uptake inside the hydrogel remained ~200% for 6 days and the degradation was completed in 12 days in physiological media. The ACP copolymer solution could form a hydrogel at body temperature (~37 °C) and could return to the solution phase if the temperature decreased below 25o °C. Fibroblast encapsulated in situ in the ACP hydrogel maintained their viability (≥90% based on the live/dead assay) for 7 days, demonstrating the good biocompatibility of the ACP hydrogel for long-term cell cultivation. In addition, three-dimensional (3D) culture showed that fibroblast attached to the hydrogels and successfully mimicked the porous structure of the ACP hydrogel after 5 days of culture. Fibroblast cells could migrate from the cell-ACP clusters and form a confluent cell layer on the surface of the culture dish. Altogether, the obtained results indicate that the thermal-responsive ACP hydrogel synthesised in this study may serve as a cellular delivery platform for diverse tissue engineering applications.


Assuntos
Alginatos/farmacologia , Antibacterianos/farmacologia , Cistamina/química , Poloxâmero/química , Alginatos/química , Antibacterianos/química , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Hidrogéis/química , Injeções , Termodinâmica , Engenharia Tecidual
18.
ACS Appl Mater Interfaces ; 13(31): 36926-36937, 2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34319074

RESUMO

Synergistic therapy holds promising potential in cancer treatment. Here, the inclusion of catechol moieties, a disulfide cross-linked structure, and pendent carboxyl into the network of polymeric nanogels with glutathione (GSH)-responsive dissociation and pH-sensitive release is first disclosed for the codelivery of doxorubicin (DOX) and bortezomib (BTZ) in synergistic cancer therapy. The pendent carboxyl groups and catechol moieties are exploited to absorb DOX through electrostatic interaction and conjugate BTZ through boronate ester, respectively. Both electrostatic interactions and boronate ester are stable at neutral or alkaline pH, while they are instable in an acidic environment to further recover the activities of BTZ and DOX. The polymeric nanogels possess a superior stability to prevent the premature leakage of drugs in a physiological environment, while their structure is destroyed in response to a typical endogenous stimulus (GSH) to unload drugs. The dissociation of the drug-loaded nanogels accelerates the intracellular release of DOX and BTZ and further enhances the therapeutic efficacy. In vitro and in vivo investigations revealed that the dual-drug loaded polymeric nanogels exhibited a strong ability to suppress tumor growth. This study thus proposes a new perspective on the production of multifunctional polymeric nanogels through the introduction of different functional monomers.


Assuntos
Antineoplásicos/uso terapêutico , Bortezomib/uso terapêutico , Doxorrubicina/uso terapêutico , Portadores de Fármacos/química , Nanogéis/química , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/química , Bortezomib/química , Catecóis/química , Cistamina/análogos & derivados , Cistamina/metabolismo , Doxorrubicina/química , Combinação de Medicamentos , Sinergismo Farmacológico , Feminino , Glutationa/metabolismo , Humanos , Células MCF-7 , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias/metabolismo , Neoplasias/patologia , Polímeros/química , Ensaios Antitumorais Modelo de Xenoenxerto
19.
ACS Appl Mater Interfaces ; 13(30): 35431-35443, 2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34304556

RESUMO

Stent implantation is the primary method used to treat coronary heart disease. However, it is associated with complications such as restenosis and late thrombosis. Despite surface modification being an effective way to improve the biocompatibility of stents, the current research studies are not focused on changes in the vascular microenvironment at the implantation site. In the present study, an adaptive drug-loaded coating was constructed on the surface of vascular stent materials that can respond to oxidative stress at the site of vascular lesions. Two functional molecules, epigallocatechin gallate (EGCG) and cysteine hydrochloride, were employed to fabricate a coating on the surface of 316L stainless steel. In addition, the coating was used as a drug carrier to load pitavastatin calcium. EGCG has antioxidant activity, and pitavastatin calcium can inhibit smooth muscle cell proliferation. Therefore, EGCG and pitavastatin calcium provided a synergistic anti-inflammatory effect. Moreover, the coating was cross-linked using disulfide bonds, which accelerated the release of the drug in response to reactive oxygen species. A positive correlation was observed between the rate of drug release and the degree of oxidative stress. Collectively, this drug-loaded oxidative stress-responsive coating has been demonstrated to significantly inhibit inflammation, accelerate endothelialization, and reduce the risk of restenosis of vascular stents in vivo.


Assuntos
Stents Farmacológicos , Espécies Reativas de Oxigênio/antagonistas & inibidores , Animais , Catequina/administração & dosagem , Catequina/análogos & derivados , Catequina/química , Catequina/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Materiais Revestidos Biocompatíveis/química , Materiais Revestidos Biocompatíveis/farmacologia , Reestenose Coronária/prevenção & controle , Cistamina/administração & dosagem , Cistamina/química , Liberação Controlada de Fármacos , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Masculino , Miócitos de Músculo Liso/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Quinolinas/administração & dosagem , Quinolinas/química , Quinolinas/farmacologia , Coelhos , Ratos Sprague-Dawley , Aço Inoxidável/química
20.
Sci Rep ; 11(1): 11946, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099759

RESUMO

The detailed pathogenesis of eosinophilic bronchitis (EB) remains unclear. Transglutaminase 2 (TG2) has been implicated in many respiratory diseases including asthma. Herein, we aim to assess preliminarily the relationship of TG2 with EB in the context of the development of an appropriate EB model through ovalbumin (OVA) sensitization and challenge in the C57BL/6 mouse strain. Our data lead us to propose a 50 µg dose of OVA challenge as appropriate to establish an EB model in C57BL/6 mice, whereas a challenge with a 400 µg dose of OVA significantly induced asthma. Compared to controls, TG2 is up-regulated in the airway epithelium of EB mice and EB patients. When TG2 activity was inhibited by cystamine treatment, there were no effects on airway responsiveness; in contrast, the lung pathology score and eosinophil counts in bronchoalveolar lavage fluid were significantly increased whereas the cough frequency was significantly decreased. The expression levels of interleukin (IL)-4, IL-13, IL-6, mast cell protease7 and the transient receptor potential (TRP) ankyrin 1 (TRPA1), TRP vanilloid 1 (TRPV1) were significantly decreased. These data open the possibility of an involvement of TG2 in mediating the increased cough frequency in EB through the regulation of TRPA1 and TRPV1 expression. The establishment of an EB model in C57BL/6 mice opens the way for a genetic investigation of the involvement of TG2 and other molecules in this disease using KO mice, which are often generated in the C57BL/6 genetic background.


Assuntos
Bronquite/imunologia , Modelos Animais de Doenças , Eosinófilos/imunologia , Proteínas de Ligação ao GTP/imunologia , Transglutaminases/imunologia , Animais , Asma/induzido quimicamente , Asma/imunologia , Bronquite/induzido quimicamente , Bronquite/metabolismo , Cistamina/farmacologia , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Eosinófilos/efeitos dos fármacos , Eosinófilos/metabolismo , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Ovalbumina , Proteína 2 Glutamina gama-Glutamiltransferase , Canal de Cátion TRPA1/genética , Canal de Cátion TRPA1/imunologia , Canal de Cátion TRPA1/metabolismo , Transglutaminases/genética , Transglutaminases/metabolismo
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