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1.
Sci Rep ; 12(1): 19243, 2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36357454

RESUMO

Anti-oxidative intraocular irrigating solutions (IISs) based on reactive persulfides, such as oxidized glutathione disulfide (GSSG), are commonly used worldwide. However, even with GSSG-based IISs, it has been shown that oxidative stress can occur during surgery, posing a risk to intraocular tissues. This study compared two IISs: one containing GSSG and one containing an oxidized glutathione trisulfide (GSSSG). Experimental in vivo irrigation with the IISs in rabbits showed that there was less leakage into the anterior chamber of rabbit serum albumin during perfusion with a 300-µM GSSSG IIS than with a 300-µM GSSG IIS. Experimental in vivo cataract surgery in rabbits showed that aqueous flare was suppressed 3 days after surgery with a 600-µM GSSSG IIS, but not with a 300-µM GSSSG or 300-µM GSSG IIS. Furthermore, an in vitro experiment, without any live tissue, showed that reactive oxygen species were suppressed more strongly with a 600-µM GSSSG IIS than with a 300-µM GSSG IIS. Thus, this study found that novel IISs based on GSSSG had anti-inflammatory and anti-oxidative effects during and after intraocular surgery and may decrease the rate of complications after surgery.


Assuntos
Extração de Catarata , Sulfetos , Animais , Coelhos , Dissulfeto de Glutationa , Sulfetos/farmacologia , Glutationa , Humor Aquoso
2.
ACS Appl Mater Interfaces ; 14(45): 50637-50648, 2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36326806

RESUMO

Photothermal therapy (PTT) has emerged as a promising alternative or supplement to cancer treatments. While PTT induces the ablation of solid tumors, its efficiency is hampered by self-recovery within impaired cancer cells through glycolysis and respiration metabolism. Based on this, the introduction of hydrogen sulfide (H2S)-mediated respiration inhibition is a good choice to make up for the PTT limitation. Herein, nanovesicles (NP1) are integrated by a hypoxia-responsive conjugated polymer (P1), polymetric H2S donor (P2), and near-infrared (NIR) light-harvesting aza-BODIPY dye (B1) for the delivery of H2S and synergistic H2S gas therapy/PTT. The scaffold of NP1 undergoes disassembly in the hypoxic environments, thus triggering the hydrolysis of P2 to continuously long-term release H2S. Dependent on the superior photothermal ability of B1, NP1 elicits high photothermal conversion efficiency (η = 19.9%) under NIR light irradiation for PTT. Moreover, NP1 serves as in situ H2S bombers in the hypoxic tumor environment and suppresses the mitochondrial respiration through inhibiting expression of cytochrome c oxidase (COX IV) and cutting off the adenosine triphosphate (ATP) generation. Both in vitro and in vivo results demonstrate good antitumor efficacy of H2S gas therapy/PTT, which will be recommended as an advanced strategy for cancer therapeutics.


Assuntos
Sulfeto de Hidrogênio , Nanopartículas , Neoplasias , Humanos , Fototerapia , Terapia Fototérmica , Sulfeto de Hidrogênio/farmacologia , Neoplasias/terapia , Hipóxia , Respiração , Hidrogênio , Sulfetos/farmacologia , Linhagem Celular Tumoral
3.
Biochem Biophys Res Commun ; 635: 291-298, 2022 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-36327916

RESUMO

Colorectal cancer is one of the most common malignancies causing the majority of cancer-related deaths. There is an urgent need to develop new anticancer modalities. Recently, efforts have been made to turn clinically approved drugs into anticancer agents in specific tumor microenvironments via NPs. Disulfiram (DSF) as an effective copper (Cu2+)-dependent anti-tumour drug, which has been more widely used in antitumor research. Here, we constructed a novel therapeutic nanoplatforms, DSF@CuS, by encapsulating DSF in hollow CuS NPs to enable in situ chemoselective activation of DSF and hyperthermal amplified chemotherapy. The anticancer effect of DSF was enhanced by the thermal energy generated under NIR irradiation through the intrinsic photothermal conversion of CuS. As a result, significant apoptosis was induced in vitro, and tumor elimination was achieved in vivo. Collectively, DSF@CuS combined with photothermal therapy can significantly promote the apoptosis of CT26 colorectal cancer cells both in vitro and in vivo, providing a potential theoretical agent for the treatment of colorectal cancer.


Assuntos
Antineoplásicos , Neoplasias Colorretais , Nanopartículas , Humanos , Dissulfiram/farmacologia , Cobre/farmacologia , Linhagem Celular Tumoral , Nanopartículas/uso terapêutico , Sulfetos/farmacologia , Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Microambiente Tumoral
4.
Appl Microbiol Biotechnol ; 106(23): 7879-7890, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36303083

RESUMO

Methanotrophs are bacteria capable on growing on methane as their sole carbon source. They may provide a promising route for upgrading natural gas into more valuable fuels and chemicals. However, natural gas may contain significant quantities of hydrogen sulfide. Little is known about how hydrogen sulfide affects the growth and physiology of methanotrophs aside from a few studies showing that it is inhibitory. This study investigated how hydrogen sulfide affects the growth and physiology of the model methanotroph, Methylococcus capsulatus Bath. Growth studies demonstrated that hydrogen sulfide inhibits the growth of M. capsulatus Bath when the concentration exceeds 0.5% (v/v). To better understand how hydrogen sulfide is inhibiting the growth of M. capsulatus Bath, transcription and metabolite concentrations were profiled using RNA sequencing and gas chromatography-mass spectrometry, respectively. Our analysis of the differentially expressed genes and changes in metabolite concentrations suggests that hydrogen sulfide inhibits cellular respiration. The cells respond to sulfide stress in part by increasing the rate of sulfide oxidation and by increasing the expression of sulfide quinone reductase and a putative persulfide dioxygenase. In addition, they reduce the expression of the native calcium-dependent methanol dehydrogenase and increase the expression of XoxF, a lanthanide-dependent methanol dehydrogenase. While the reason of this switch in unknown, XoxF has previously been shown to be induced by lanthanides or nitric oxide in methanotrophs. Collectively, these results further our understanding of how methanotrophs respond to sulfide stress and may aid in the engineering of strains resistant to hydrogen sulfide. KEY POINTS: • Hydrogen sulfide inhibits growth of Methylococcus capsulatus Bath • Sulfide stress inhibits cellular respiration • Sulfide stress induces XoxF, a lanthanide-dependent methanol dehydrogenase.


Assuntos
Sulfeto de Hidrogênio , Elementos da Série dos Lantanídeos , Methylococcus capsulatus , Methylococcus capsulatus/genética , Methylococcus capsulatus/metabolismo , Sulfeto de Hidrogênio/metabolismo , Gás Natural , Proteínas de Bactérias/metabolismo , Metano/metabolismo , Elementos da Série dos Lantanídeos/metabolismo , Análise de Sistemas , Sulfetos/farmacologia , Sulfetos/metabolismo , Oxigenases/metabolismo
5.
Nitric Oxide ; 129: 41-52, 2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-36216240

RESUMO

Hydrogen sulfide (H2S) emerged as an essential signaling molecule exerting beneficial effects in various cardiovascular, neurodegenerative, or musculoskeletal diseases with an inflammatory component, such as osteoarthritis. These protective effects were initially attributed to protein S-sulfhydration, a posttranslational modification of reactive cysteine residues. However, recent studies suggest that polysulfides and not H2S are responsible for S-sulfhydration. To distinguish between H2S and polysulfide-mediated effects in this study, we used the slow-releasing H2S and persulfide donor P*, which can be decomposed into polysulfides. The effects of P* on IL-1ß-induced inducible nitric oxide synthase (iNOS), a pro-inflammatory mediator in osteoarthritis, were determined by nitrite measurement, qPCR, and Western blotting in the murine chondrocyte-like cell line ATDC5. Decomposed P* significantly reduced IL-1ß-induced iNOS signaling via polysulfides, independently of H2S. In line with this, the fast-releasing H2S donor NaHS was ineffective. In RAW 264.7 macrophages, similar results were obtained. P*-derived polysulfides further diminished IL-1ß-induced CCAAT/enhancer-binding protein (C/EBP) ß and δ expression in ATDC5 cells, which might play a critical role in P*-mediated iNOS decline. In conclusion, our data support the view that polysulfides are essential signaling molecules as well as potential mediators of H2S signaling. Moreover, we propose that C/EBPß/δ might be a novel target involved in H2S and polysulfide-mediated anti-inflammatory signaling.


Assuntos
Sulfeto de Hidrogênio , Osteoartrite , Camundongos , Animais , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Sulfetos/farmacologia , Sulfetos/metabolismo , Anti-Inflamatórios , Óxido Nítrico/metabolismo
6.
J Med Chem ; 65(20): 14221-14236, 2022 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-36256884

RESUMO

Due to the emergence of antimicrobial resistance and the lack of new antibacterial agents, it has become urgent to discover and develop new antibacterial agents against multidrug-resistant pathogens. Antimicrobial peptides (AMPs) serve as the first line of defense for the host. In this work, we have designed, synthesized, and biologically evaluated a series of phenyl sulfide derivatives by biomimicking the structural features and biological functions of AMPs. Among these derivatives, the most promising compound 17 exhibited potent antibacterial activity against Gram-positive bacteria (minimum inhibitory concentrations = 0.39-1.56 µg/mL), low hemolytic activity (HC50 > 200 µg/mL), and high membrane selectivity. In addition, 17 can rapidly kill Gram-positive bacteria within 0.5 h through membrane-targeting action and avoid antibiotic resistance. More importantly, 17 showed high in vivo efficacy against Staphylococcus aureus in a murine corneal infection model. Therefore, 17 has great potential as a lead compound for the treatment of Gram-positive bacterial infections.


Assuntos
Anti-Infecciosos , Bactérias Gram-Positivas , Camundongos , Animais , Testes de Sensibilidade Microbiana , Antibacterianos/química , Cátions , Sulfetos/farmacologia , Sulfetos/uso terapêutico
7.
J Med Chem ; 65(20): 13681-13691, 2022 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-36257066

RESUMO

Fatty acid synthase (FASN), a sole cytosolic enzyme responsible for de-novo lipid synthesis, is overexpressed in cancer but not in normal non-lipogenic tissues. FASN has been targeted, albeit no such inhibitor has been approved. Proton pump inhibitors (PPIs), approved for digestive disorders, were found to inhibit FASN with anticancer activities in attempting to repurpose Food and Drug Administration-approved drugs. Indeed, PPI usage benefited breast cancer patients and increased their response rate. Due to structural similarity, we thought that their metabolites might extend anticancer effects of PPIs by inhibiting FASN. Here, we tested this hypothesis and found that 5-hydroxy lansoprazole sulfide (5HLS), the end lansoprazole metabolite, was more active than lansoprazole in inhibiting FASN function and regulation of NHEJ repair of oxidative DNA damage via PARP1. Surprisingly, 5HLS inhibits the enoyl reductase, whereas lansoprazole inhibits the thioesterase of FASN. Thus, PPI metabolites may contribute to the lasting anticancer effects of PPIs by inhibiting FASN.


Assuntos
Inibidores da Bomba de Prótons , Neoplasias de Mama Triplo Negativas , Humanos , Lansoprazol/farmacologia , Lansoprazol/uso terapêutico , Inibidores da Bomba de Prótons/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Oxirredutases , Ácido Graxo Sintases/metabolismo , Sulfetos/farmacologia , Lipídeos
8.
Invest New Drugs ; 40(6): 1231-1243, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36287298

RESUMO

Acute promyelocytic leukemia (APL) is liable to induce disseminated intravascular coagulation and has a high early mortality. Although the combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has significantly improved the complete remission rate, there are still some patients developed drug resistance. Growing evidence suggests that natural killer (NK) cell-mediated immunotherapy as a new treatment can help slow the progression of hematological malignancies. Previous studies also indicated that some tumors exhibited excellent responsiveness to NK cells in vitro. However, many clinical trial results showed that the anti-tumor effect of NK cells infusion alone was not ideal, which may be related to the inactivation of infiltrating NK cells caused by strong immunosuppression in tumor microenvironment, but the specific mechanism remains to be further explored. In the present study, we demonstrated that low doses of tetra-arsenic tetra-sulfide (As4S4) not only enhanced the in vitro killing of NK-92MI against ATRA-resistant APL cells, but also strengthened the growth inhibition of xenografted tumors in APL mouse model. Mechanistically, As4S4 altered the expression of natural killer group 2 member D ligands (NKG2DLs) and cytokines in APL cells, and PD-1 in NK-92MI cells. In addition, database retrieval results further revealed the relationship between the differentially regulated molecules of As4S4 and immune infiltration and its impact on prognosis. In conclusion, our findings confirmed the potential of As4S4 as an adjuvant for NK-92MI in the treatment of ATRA-resistant APL.


Assuntos
Arsênio , Arsenicais , Leucemia Promielocítica Aguda , Animais , Camundongos , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patologia , Arsênio/uso terapêutico , Arsenicais/farmacologia , Arsenicais/uso terapêutico , Tretinoína/farmacologia , Tretinoína/uso terapêutico , Sulfetos/farmacologia , Sulfetos/uso terapêutico , Imunoterapia , Óxidos/farmacologia , Óxidos/uso terapêutico , Microambiente Tumoral
9.
Molecules ; 27(17)2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36080497

RESUMO

Aqueous root extract from Acanthopanax senticosus (ASRE) has a wide range of medicinal effects. The present work was aimed at studying the influence of sulfide, cysteine and glutathione on the antioxidant properties of ASRE and some of its selected phytochemical components. Reduction of the 2-(4-carboxyphenyl)-4,5-dihydro-4,4,5,5-tetramethyl-1H-imidazol-1-yloxy-3-oxide (●cPTIO) stable radical and plasmid DNA (pDNA) cleavage in vitro assays were used to evaluate antioxidant and DNA-damaging properties of ASRE and its individual components. We found that the interaction of ASRE and its two components, caffeic acid and chlorogenic acid (but not protocatechuic acid and eleutheroside B or E), with H2S/HS-, cysteine or glutathione significantly increased the reduction of the ●cPTIO radical. In contrast, the potency of ASRE and its selected components was not affected by Na2S4, oxidized glutathione, cystine or methionine, indicating that the thiol group is a prerequisite for the promotion of the antioxidant effects. ASRE interacting with H2S/HS- or cysteine displayed a bell-shaped effect in the pDNA cleavage assay. However, ASRE and its components inhibited pDNA cleavage induced by polysulfides. In conclusion, we suggest that cysteine, glutathione and H2S/HS- increase antioxidant properties of ASRE and that changes of their concentrations and the thiol/disulfide ratio can influence the resulting biological effects of ASRE.


Assuntos
Eleutherococcus , Sulfeto de Hidrogênio , Antioxidantes/química , Antioxidantes/farmacologia , Cisteína , DNA , Eleutherococcus/química , Glutationa , Sulfeto de Hidrogênio/química , Extratos Vegetais/farmacologia , Plasmídeos/genética , Sulfetos/farmacologia
10.
Mol Biol (Mosk) ; 56(5): 697-709, 2022.
Artigo em Russo | MEDLINE | ID: mdl-36165011

RESUMO

Counteraction of the origin and distribution of multidrug-resistant pathogens responsible for intra-hospital infections is a worldwide issue in medicine. In this brief review, we discuss the results of our recent investigations, which argue that many antibiotics, along with inactivation of their traditional biochemical targets, can induce oxidative stress (ROS production), thus resulting in increased bactericidal efficiency. As we previously showed, hydrogen sulfide, which is produced in the cells of different pathogens protects them not only against oxidative stress but also against bactericidal antibiotics. Next, we clarified the interplay of oxidative stress, cysteine metabolism, and hydrogen sulfide production. Finally, demonstrated that small molecules, which inhibit a bacterial enzyme involved in hydrogen sulfide production, potentiate bactericidal antibiotics including quinolones, beta-lactams, and aminoglycosides against bacterial pathogens in in vitro and in mouse models of infection. These inhibitors also suppress bacterial tolerance to antibiotics by disrupting the biofilm formation and substantially reducing the number of persister bacteria, which survive the antibiotic treatment. We hypothesise that agents which limit hydrogen sulfide biosynthesis are effective tools to counteract the origin and distribution of multidrug-resistant pathogens.


Assuntos
Sulfeto de Hidrogênio , Quinolonas , Aminoglicosídeos/farmacologia , Animais , Antibacterianos/farmacologia , Bactérias , Cisteína , Sulfeto de Hidrogênio/farmacologia , Camundongos , Quinolonas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Sulfetos/farmacologia , beta-Lactamas/farmacologia
11.
ACS Nano ; 16(9): 14860-14873, 2022 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-36094899

RESUMO

Owing to its flexibility and high treatment efficiency, phototherapy is rapidly emerging for treating bacteria-induced diseases, but how to improve the sensitivity of bacteria to reactive oxygen species (ROS) and heat simultaneously to kill bacteria under mild conditions is still a challenge. Herein, we designed a NIR light catalyst (Bi2S3-S-nitrosothiol-acetylcholine (BSNA)) by transforming •O2- into peroxynitrite in situ, which can enhance the bacterial sensibility to ROS and heat and kill bacteria under a mild temperature. The transformed peroxynitrite in situ possessed a stronger ability to penetrate cell membranes and antioxidant capacity. The BSNA nanoparticles (NPs) inhibited the bacterial glucose metabolic process through down-regulated xerC/xerD expression and disrupted the HSP70/HSP90 secondary structure through nitrifying TYR179. Additionally, the synergistic effect of the designed BSNA and clinical antibiotics increased the antibacterial activity. In the case of tetracycline-class antibiotics, BSNA NPs induced phenolic hydroxyl group structure changes and inhibited the interaction between tetracycline and targeted t-RNA recombinant protein. Besides, BSNA stimulated production of more CD8+ T cells and reduced common complications in peritonitis, which provided immunotherapy activity. The targeted and anti-infective effect of BSNA suggested that we propose a nanotherapeutic strategy to achieve more efficient synergistic therapy under mild temperatures.


Assuntos
Infecções Bacterianas , Nanopartículas , S-Nitrosotióis , Acetilcolina , Antibacterianos/química , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Antioxidantes , Bactérias/metabolismo , Infecções Bacterianas/tratamento farmacológico , Bismuto , Linfócitos T CD8-Positivos , Glucose , Humanos , Imunoterapia , Nanopartículas/química , Ácido Peroxinitroso , Fototerapia , RNA , Espécies Reativas de Oxigênio/metabolismo , Proteínas Recombinantes , Sulfetos/química , Sulfetos/farmacologia , Sulfetos/uso terapêutico , Tetraciclinas
12.
Artigo em Chinês | MEDLINE | ID: mdl-36052584

RESUMO

Objective: To investigate the protective effect of diallyl sulfide (DAS) , against benzene-induced genetic damage in rat. Methods: In September 2018, Sixty adult male adaptive feeding 5 days, were randomly divided into six groups according to their weight. Control groups, DAS control groups, benzene model groups, benzene+low DAS groups, benzene+middle DAS groups, benzene+High DAS group, 10 in each group. Rats in the DAS and DAS control group were orally given DAS at 40, 80, 160, 160 mg/kg, blank control and benzene model groups were given corn oil in the same volume. 2 h later, the rats in the benzene model and DAS treatment groups were given gavage administration of benzene (1.3 g/kg) mixed with corn oil (50%, V/V) , blank and DAS control groups were given corn oil in the same volume. Once a day, for 4 weeks. Samples were collected for subsequent testing. Results: Compared with the blank control group, In benzene treated rat, peripheral WBC count was reduced 65.06% (P=0.003) , lymphocyte ratiowas reduced (P=0.000) , micronucleus rate was increased (P=0.000) , Mean fluorescent intensity and relative fluorescence intensity of γH2AX in BMCs were increased 32.69%、32.64% (P=0.001、0.008) , Mean fluorescent intensity and relative fluorescence intensity of γH2AX in PBLs were increased 397.70%、396.26% (P=0.000、P=0.003) respectively. Compared with the benzene model group, the WBC count increased respectively (P=0.000、0.003、0.006) and the micronucleus rate decreased (P=0.000、0.000、0.000) in the DAS groups, Mean fluorescent intensity and relative fluorescence intensity ofγH2AX in BMCs were significantly reduced in the high DAS groups (P=0.000、0.000) , Mean fluorescent intensity and relative fluorescence intensity ofγH2AX in PBLs were significantly reduced in the low, middle, high DAS groups (P=0.000、0.000) . Conclusion: DAS can effectively suppress benzene induced genotoxic damage in rats.


Assuntos
Compostos Alílicos , Benzeno , Ácido 4-Acetamido-4'-isotiocianatostilbeno-2,2'-dissulfônico/análogos & derivados , Compostos Alílicos/farmacologia , Animais , Benzeno/toxicidade , Óleo de Milho , Dano ao DNA , Masculino , Ratos , Sulfetos/farmacologia
13.
Biosci Biotechnol Biochem ; 86(11): 1552-1561, 2022 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-36073357

RESUMO

Garlic is a popular culinary herb for the prevention and treatment of alcoholic liver disease (ALD). Diallyl Trisulfide (DATS) is the major organosulfur compound of garlic. Latest studies indicated that the hepatocyte pyroptosis serves a primary role in the pathogenesis of ALD. The present study aims to assess the inhibitory effect of DATS on alcohol-induced hepatocyte pyroptosis, and to elucidate the potential mechanism by using the hepatocyte cell line HL-7702. Our study found that DATS inhibited alcohol-induced pyroptosis by decreasing gasdermin D (GSDMD) activation. Results illuminated that DATS inhibited alcohol-induced (NOD)-like receptor containing pyrin domain 3 (NLRP3) inflammasome activation by reducing intracellular reactive oxygen species (ROS) accumulation. Furthermore, DATS upregulated hydrogen sulfide (H2S) to resist ROS overproduction. The present study demonstrated that DATS mitigated alcohol-induced hepatocyte pyroptosis by increasing the intracellular level of H2S.


Assuntos
Compostos Alílicos , Alho , Sulfeto de Hidrogênio , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Piroptose , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Apoptose , Compostos Alílicos/farmacologia , Sulfetos/farmacologia , Hepatócitos/metabolismo , Etanol , Antioxidantes/farmacologia
14.
Ecotoxicol Environ Saf ; 245: 114108, 2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-36174319

RESUMO

CuInS2/ZnS-PEG quantum dots (QDs) are among the most widely used near infrared non-cadmium QDs and are favored because of their non-cadmium content and strong tissue penetration. However, with their increasing use, there is great concern about whether exposure to QDs is potentially risky to the environment and humans. Furthermore, toxicological data related to CuInS2/ZnS-PEG QDs are scarce. In the study, we found that CuInS2/ZnS-PEG QDs (0-100 µg/mL) could internalize into human LAD2 mast cells without affecting their survival rate, nor did it cause degranulation or release of IL-8 and TNF-α. However, CuInS2/ZnS-PEG QDs significantly inhibited Substance P (SP) and LL-37-induced degranulation and chemotaxis of LAD2 cells by inhibiting calcium mobilization. Lower concentrations of CuInS2/ZnS-PEG QDs promoted the release of TNF-α and IL-8 stimulated by SP, but higher concentrations of CuInS2/ZnS-PEG QDs significantly inhibited the release of TNF-α and IL-8. On the other hand, CuInS2/ZnS-PEG QDs promoted LL-37-mediated TNF-α release from LAD2 cells in a dose-dependent manner from 6.25 to 100 µg/mL, while release of IL-8 triggered by LL-37 was dose-dependently inhibited within a dose concentration of 12.5-100 µg/mL. Collectively, our data demonstrated that CuInS2/ZnS-PEG QDs differentially mediated human mast cell activation induced by SP and LL-37.


Assuntos
Pontos Quânticos , Cálcio , Defeitos Congênitos da Glicosilação , Cobre , Humanos , Interleucina-8 , Mastócitos , Polietilenoglicóis , Pontos Quânticos/toxicidade , Substância P , Sulfetos/farmacologia , Fator de Necrose Tumoral alfa , Compostos de Zinco/toxicidade
15.
Chemosphere ; 308(Pt 2): 136232, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36055592

RESUMO

Anaerobic ammonium oxidation (anammox) has evolved as a carbon and energy-efficient nitrogen management bioprocess. However, factors such as inhibitory chemicals still challenge the easy operation of this powerful bioprocess. This research systematically evaluated the inhibition kinetics of sulfide, nitrite, and recalcitrant carbon under a genomic framework. The inhibition at the substrate and genetic levels of sulfide, nitrite and recalcitrant carbon on anammox activity was studied using batch tests. Nitrite inhibition of anammox followed substrate inhibition and was best described by the Aiba model with an inhibition coefficient [Formula: see text] of 324.04 mg N/L. Hydrazine synthase (hzsB) gene (anammox biomarker) expression was increased over time when incubated with nitrite up to 400 mg N/L. However, despite having the highest specific nitrite removal (SNR), the expression of hzsB at 100 and 200 mg N/L of nitrite was more muted than in most other samples with lower SNRs. Sulfide severely inhibited anammox activities. The inhibition was fitted with a Monod-based model with a [Formula: see text] of 4.39 mg S/L. At a sulfide concentration of 5 mg/L, the hzsB expression decreased throughout the experiment from its original value at he beginning. Recalcitrant carbon of filtrate from thermal hydrolysis process pretreated anaerobic digester had a minimal effect on maximum specific anammox activity (MSAA), and thus the value of the inhibition coefficient could not be calculated. At the same time, its hzsB expression profile was similar to that in the control. Resiliency and recovery tests indicated that the inhibition of nitrite (up to 400 mg N/L) and recalcitrant carbon (in 100% filtrate) were reversible. About 32% of MSAA was recovered after repeated exposures to sulfide at 2.5 mg/L, while at 5 mg/L, the inhibition was irreversible. Findings from this study will be helpful for the successful design and implementation of anammox in full-scale applications.


Assuntos
Compostos de Amônio , Nitritos , Compostos de Amônio/metabolismo , Oxidação Anaeróbia da Amônia , Anaerobiose , Biomassa , Reatores Biológicos , Carbono , Expressão Gênica , Hidrazinas , Nitritos/metabolismo , Nitrogênio , Sulfetos/farmacologia
16.
Eur J Med Chem ; 243: 114761, 2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36179403

RESUMO

Lymphomas are still difficult to treat even with modern therapies as, among others, multidrug resistance (MDR) is often counteracting a successful cancer therapy. P-gp/ABC-transporters are well-known for their crucial role in the main tumour MDR mechanism, eliminating drugs and cytotoxic substances from the cancer cell by efflux, and their modulators are promising for innovative therapy, but none has been approved in the pharmaceutical market yet. Herein, we have designed, synthesised and analysed 30 novel seleno- and thioether 1,3,5-triazine derivatives conducting comprehensive studies to evaluate their potential application in human JURKAT lymphoma cells. Among the new compounds, four (11, 12, 13 and 23) were much more effective than the reference inhibitor verapamil, being potent ABCB1 inhibitors already at 2 µM, while 5 and 15 showed very potent ABCB1 inhibitory activity only at 20 µM. Results of P-gp ATPase assays, supported with docking studies, indicated the competitive substrate mode of modulating action for 15, while ABCB1, ABCC1 and ABCG2 genes expression induction by 15 with q-PCR was confirmed. All compounds were evaluated for their cytotoxic and antiproliferative properties in both sensitive (PAR) and resistant (MDR) mouse T-lymphoma cell lines, and compound 15, also considering its promising ABCB1 inhibition properties, was revealed to be the best compound in terms of its cytotoxic effect (IC50: 16.73 µM) as well as concerning the antiproliferative effect (IC50: 5.35 µM) in MDR cells. Regarding the mechanistic studies looking at the cell cycle, the thioether 15 and selenium derivatives 26 and 29 were significantly effective in the regulation of cell cycle-related genes alone or in co-treatment with doxorubicin counteracting Cyclin D1 and E1 expression and increasing p53 and p21 levels, shedding first light on their mechanism of action. In summary, we explored the chemical space of seleno- and thioether 1,3,5-triazine derivatives with interesting activity against lymphoma. Especially compound 15 is worthy of being studied deeper to evaluate its precise mode of action further as well it can be improved regarding its potency and drug-likeness.


Assuntos
Antineoplásicos , Linfoma , Camundongos , Animais , Humanos , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Sulfetos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Proteínas de Neoplasias , Resistência a Múltiplos Medicamentos , Antineoplásicos/farmacologia , Antineoplásicos/química , Linfoma/tratamento farmacológico , Preparações Farmacêuticas , Triazinas/farmacologia , Linhagem Celular Tumoral
17.
J Ethnopharmacol ; 298: 115610, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-35973632

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Niu Huang Jie Du prescription (NHJD) is a traditional Chinese medicine (TCM) widely used in patients suffering from excessive inner fire toxin (Huo Du Nei Sheng) syndrome, such as sore throat, gingival swelling, and pain, mouth and tongue sores, etc. This formula contains realgar (As4S4) which is one of the 28 toxic medicinal materials promulgated by the Chinese Ministry of Health. Many studies reported its toxicity on the liver and kidney, and the detoxification effect of NHJD. However, its detoxification mechanism is still unclear. AIM OF THE STUDY: To clarify the detoxification mechanism of NHJD to realgar, this study evaluated the detoxification effect of NHJD on realgar exposure in mice, and analyzed differences in mRNA expression profiles in liver tissues and associated functional predictions. MATERIAL AND METHODS: ICR mice were administered with NHJD, realgar, and CMC-Na as blank control for 12 weeks, respectively. Liver injury was evaluated by histopathologic examination and liver mRNA gene were sequenced by Illumina. Differentially expressed gene, functionally enrichment and protein association network analysis were conducted. RESULTS: 43 genes were screened out, among which 15 genes in the realgar group were decreased, but the extent of the decline has been restored in the NHJD group. The remaining 28 genes have exactly the opposite trends. Functional module analysis revealed that those detoxification function-related genes were primarily for positive regulation of glutathione metabolism, P450 on the metabolism of exogenous compounds, oxidative stress and immune-related, etc. CONCLUSIONS: The results indicated that realgar mainly causes liver damage by changing the common enzymes of drug metabolism, especially the expression of genes related to CYPs, GSTs family, oxidative stress, and complement immunity, while the TCM prescription NHJD has a regulatory effect on the abnormal expression of corresponding genes. Our results will provide some clues for the detoxification mechanism of arsenic-containing TCM prescriptions.


Assuntos
Arsenicais , Medicamentos de Ervas Chinesas , Animais , Arsenicais/farmacologia , Medicamentos de Ervas Chinesas/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Fígado , Medicina Tradicional Chinesa/métodos , Camundongos , Camundongos Endogâmicos ICR , Prescrições , RNA/metabolismo , RNA/farmacologia , RNA Mensageiro/metabolismo , Sulfetos/farmacologia
18.
Free Radic Biol Med ; 189: 157-168, 2022 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-35921994

RESUMO

Radiotherapy is a standard-of-care treatment approach for glioblastoma (GBM) patients, but therapeutic resistance to radiotherapy remains a major challenge. Here we demonstrate that diallyl trisulfide (DATS) directly conjugates with cysteine (C) 32 and C35 (C32/35) residues of thioredoxin 1 (Trx1) through Michael addition reactions. Due to localizing in activity center of Trx1, the conjugation between DATS and C32/35 results in inhibition of Trx1 activity, therefore disturbing thioredoxin system and leading to accumulated levels of reactive oxygen species (ROS). High levels of Trx1 expression are correlated with poor prognosis of glioma patients. Notably, we reveal that DATS synergistically enhances irradiation (IR)-induced ROS accumulation, apoptosis, DNA damage, as well as inhibition of tumor growth of GBM cells. These findings highlight the potential benefits of DATS in sensitizing radiotherapy of GBM patients.


Assuntos
Compostos Alílicos , Glioblastoma , Compostos Alílicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/radioterapia , Humanos , Espécies Reativas de Oxigênio/metabolismo , Sulfetos/farmacologia , Tiorredoxinas/genética , Tiorredoxinas/metabolismo
19.
Int J Mol Sci ; 23(16)2022 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-36012477

RESUMO

Increased fructose consumption induces metabolic-syndrome-like pathologies and modulates vasoactivity and the participation of nitric oxide (NO) and hydrogen sulfide (H2S). We investigated whether a slow-releasing H2S donor, GYY-4137, could exert beneficial activity in these conditions. We examined the effect of eight weeks of fructose intake on the blood pressure, biometric parameters, vasoactive responses, and NO and H2S pathways in fructose-fed spontaneously hypertensive rats with or without three weeks of GYY-4137 i.p. application. GYY-4137 reduced triacylglycerol levels and blood pressure, but not adiposity, and all were increased by fructose intake. Fructose intake generally enhanced endothelium-dependent vasorelaxation, decreased adrenergic contraction, and increased protein expression of interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα), and concentration of conjugated dienes in the left ventricle (LV). Although GYY-4137 administration did not affect vasorelaxant responses, it restored disturbed contractility, LV oxidative damage and decreased protein expression of TNFα in fructose-fed rats. While the participation of endogenous H2S in vasoactive responses was not affected by fructose treatment, the expression of H2S-producing enzyme cystathionine ß-synthase in the LV was increased, and the stimulation of the NO signaling pathway improved endothelial function in the mesenteric artery. On the other hand, chronic treatment with GYY-4137 increased the expression of H2S-producing enzyme cystathionine γ-lyase in the LV and stimulated the beneficial pro-relaxant and anti-contractile activity of endogenous H2S in thoracic aorta. Our results suggest that sulfide and nitroso signaling pathways could trigger compensatory vasoactive responses in hypertensive rats with metabolic disorder. A slow H2S-releasing donor could partially amend metabolic-related changes and trigger beneficial activity of endogenous H2S.


Assuntos
Frutose , Sulfeto de Hidrogênio , Animais , Cistationina gama-Liase/metabolismo , Sulfeto de Hidrogênio/metabolismo , Sulfeto de Hidrogênio/farmacologia , Morfolinas , Óxido Nítrico/metabolismo , Compostos Organotiofosforados , Ratos , Ratos Endogâmicos SHR , Sulfetos/farmacologia , Fator de Necrose Tumoral alfa
20.
J Fluoresc ; 32(6): 2129-2137, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35947332

RESUMO

In the present work, CdTe/ZnS high luminescence quantum dots (QDs) were synthesized by a facile, fast, one-pot, and room temperature photochemical method. Synthesized QDs were characterized by different structural and optical analyses such as X-ray diffraction (XRD), energy dispersive X-ray spectroscopy (EDS), field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), Fourier transform-infrared spectroscopy (FT-IR), Raman, photoluminescence (PL) and UV-visible (UV-vis) spectroscopies. The results confirmed the successful growth of the ZnS shell and formation of CdTe/ZnS core/shell structure. CdTe/ZnS prepared QDs indicated a PL quantum yield of about 51%. These high luminescence QDs were used for detection of Hg2+ ions in aqueous media, as catalyst for photodegradation of different organic dyes, and as antibacterial material for the inhibition of bacterial growth. PL intensity of the CdTe/ZnS QDs was completely quenched after addition of 1 m molar Hg2+in to the media. Photocatalyst activity of CdTe/ZnS QDs was studied by rhodamine b, methylene blue, and methylene orange as organic dyes under both the sun and UV illuminations, and results showed that CdTe/ZnS QDs had the best photocatalyst activity for methylene blue degradation under UV irradiation and radical scavenger results indicated that electrons have a main role in photodegradation of methylene blue dye by CdTe/ZnS QDs under UV illumination. Antibacterial effects of CdTe/ZnS QDs evaluated by Minimum Inhibitory Concentration (MIC), and Minimum Bactericidal Concentration (MBC) methods against two strains of bacteria. The results of the antibacterial test showed that CdTe/ZnS could inhibit bacterial growth in Bacillus cereus (Gram-positive) and Escherichia coli (Gram-negative G) bacteria.


Assuntos
Compostos de Cádmio , Mercúrio , Pontos Quânticos , Pontos Quânticos/química , Compostos de Cádmio/farmacologia , Compostos de Cádmio/química , Telúrio/química , Mercúrio/análise , Espectroscopia de Infravermelho com Transformada de Fourier , Azul de Metileno , Compostos de Zinco/química , Sulfetos/farmacologia , Sulfetos/química , Água/química , Antibacterianos/farmacologia , Antibacterianos/análise , Escherichia coli , Corantes/análise
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