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1.
Environ Pollut ; 319: 120998, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36603760

RESUMO

Mineral elements and antibiotic-resistant bacterial pollutants in livestock and poultry farms' wastewater are often sources of ecological and public health problems. To understand the heavy-metal pollution status and the characteristics of drug-resistant Escherichia coli (E. coli) in swine-farm wastewater in Shandong Province and to provide guidance for the rational use of mineral-element additives, common antibiotics, and quaternary ammonium compound disinfectants on swine farms, 10 mineral elements were measured and E. coli isolated from wastewater and its resistance to 29 commonly used antibiotics and resistance genes was determined. Finally, phylogenetic and multi-locus sequence typing (MLST) analyses was performed on E. coli. The results showed serious pollution from iron and zinc, with a comprehensive pollution index of 708.94 and 3.13, respectively. It is worth noting that average iron levels in 75% (12/16) of the districts exceed allowable limits. Multidrug-resistant E. coli were found in every city of the province. The E. coli isolated from swine-farm wastewater were mainly resistant to tetracyclines (95.3%), chloramphenicol (77.8%), and sulfonamides (62.2%), while antibiotic resistance genes for quinolones, tetracyclines, sulfonamides, aminoglycosides, and ß-lactams were all more than 60%. The clonal complex 10 (CC10) was prevalent, and ST10 and ST48 were dominant in E. coli isolates. Multidrug-resistant E. coli were widely distributed, with mainly A genotypes. However, the mechanism of the effect of iron on antibiotic resistance needs more study in this area. Thus, further strengthening the prevention and control of iron and zinc pollution and standardizing the use of antibiotics and mineral element additives in the swine industry are necessary.


Assuntos
Antibacterianos , Metais Pesados , Animais , Suínos , Antibacterianos/farmacologia , Escherichia coli , Fazendas , Tipagem de Sequências Multilocus , Filogenia , Agricultura , Metais Pesados/toxicidade , Sulfanilamida/farmacologia , Tetraciclinas/farmacologia , Ferro/farmacologia , Zinco/farmacologia , China , Farmacorresistência Bacteriana Múltipla/genética , Testes de Sensibilidade Microbiana
2.
Sci Bull (Beijing) ; 68(1): 77-94, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36621435

RESUMO

Iron accumulation and lipid peroxidation form the basis of ferroptosis, potentially circumventing the limitations of apoptosis in cancer treatment. Owing to the lack of potent ferroptosis inducers, the development of efficient ferroptosis-based therapeutic agents and protocols against cancers is highly challenging. Inspired by the topological effect of nanoparticles in modulating cellular function/status, a specific tetrapod ferroptosis-inducer iron-palladium (FePd) nanocrystal was rationally engineered for physically activated autophagy-augmented ferroptosis and enhanced cancer immunotherapy. Specifically, the tetrapod FePd nanocrystal featured strong peroxidase-/glutathione oxidase-mimicking bioactivities, which promoted cancer cell ferroptosis. The special spiky morphology and nanostructure of the FePd nanocrystal simultaneously induced autophagy, which augmented ferroptosis in cancer cells and triggered the release of inflammatory cytokines in macrophages for strengthening anti-PD-L1-antibody mediated immunotherapy, synergistically achieving the maximal antineoplastic effect in three tumor-bearing animal models. This unique physical activation strategy for efficient cancer treatment via precise morphological tuning represents a paradigm for nanomedicine design for efficient tumor treatment.


Assuntos
Ferroptose , Neoplasias , Animais , Nanomedicina , Neoplasias/tratamento farmacológico , Ferro/farmacologia , Imunoterapia , Autofagia
3.
Sci Prog ; 106(1): 368504221147173, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36718538

RESUMO

Colorectal cancer (CRC) can be resistant to platinum drugs, possibly through ferroptosis suppression, albeit the need for further work to completely understand this mechanism. This work aimed to sum up current findings pertaining to oxaliplatin resistance (OR) or resistance to ascertain the potential of ferroptosis to regulate oxaliplatin effects. In this review, tumor development relating to iron homeostasis, which includes levels of iron that ascertain cells' sensitivity to ferroptosis, oxidative stress, or lipid peroxidation in colorectal tumor cells that are connected with ferroptosis initiation, especially the role of c-Myc/NRF2 signaling in regulating iron homeostasis, coupled with NRF2/GPX4-mediated ferroptosis are discussed. Importantly, ferroptosis plays a key role in OR and ferroptotic induction may substantially reverse OR in CRC cells, which in turn could inhibit the imbalance of intracellular redox induced by oxaliplatin and ferroptosis, as well as cause chemotherapeutic resistance in CRC. Furthermore, fundamental research of small molecules, ferroptosis inducers, GPX4 inhibitors, or natural products for OR coupled with their clinical applications in CRC have also been summarized. Also, potential molecular targets and mechanisms of small molecules or drugs are discussed as well. Suggestively, OR of CRC cells could significantly be reversed by ferroptosis induction, wherein this result is discussed in the current review. Prospectively, the existing literature discussed in this review will provide a solid foundation for scientists to research the potential use of combined anticancer drugs which can overcome OR via targeting various mechanisms of ferroptosis. Especially, promising therapeutic strategies, challenges ,and opportunities for CRC therapy will be discussed.


Assuntos
Neoplasias Colorretais , Ferroptose , Humanos , Platina/farmacologia , Oxaliplatina/farmacologia , Oxaliplatina/uso terapêutico , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/farmacologia , Procedimentos Clínicos , Ferro/metabolismo , Ferro/farmacologia , Neoplasias Colorretais/tratamento farmacológico
4.
J Mater Chem B ; 11(2): 415-429, 2023 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-36512437

RESUMO

Ferroptosis, a type of programmed cell death induced by the iron-dependent lipid hydroperoxide pathway, has attracted widespread attention. However, Fenton response-dependent ferroptosis has many limitations, such as insufficient reaction conditions in the tumor micro-environment. Here, we propose an all-in-one phototherapy nanoplatform consisting of iron-polydopamine (Fe-PDA), a folic acid-modified red blood cell membrane (FA-RBCm), and epirubicin (EPI), namely, Fe-PDA-EPI@FA-RBCm NPs, to achieve enhanced photothermal-ferroptosis effects via overcoming the limitations of the Fenton-like reaction. The results showed that the synthesized biomimetic nanoparticles could decompose hydrogen peroxide (H2O2) to generate hydroxyl radicals (˙OH), and further induce the non-apoptotic ferroptosis pathway. After irradiation with near-infrared (NIR) light, the uptake of Fe-PDA-EPI@FA-RBCm NPs by cells could be effectively promoted, and it presented impressive in vitro and in vivo photothermal properties. In vitro and in vivo results showed that laser irradiation could enhance ferroptosis by promoting the production of reactive oxygen species (ROS) and lipid peroxides, down-regulating the expression of glutathione peroxidase 4 (GPX4), and reducing the mitochondrial membrane potential. Furthermore, the photothermal-promoted ferroptosis and apoptosis pathways (photothermal therapy and chemotherapy) exhibited outstanding synergistic antitumor efficacy in vitro and in vivo, with an in vivo tumor inhibition rate as high as 76.95%. In conclusion, the construction of tumor-targeted biomimetic nanocarriers utilizing the advantageous properties of RBCm has been investigated as a potential anticancer strategy.


Assuntos
Ferroptose , Nanopartículas , Neoplasias , Peróxido de Hidrogênio/farmacologia , Nanopartículas/uso terapêutico , Apoptose , Epirubicina/farmacologia , Ferro/farmacologia
5.
J Inorg Biochem ; 238: 112023, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36270041

RESUMO

Lactobacillaceae are a diverse family of lactic acid bacteria found in the gut microbiota of humans and many animals. These bacteria exhibit beneficial effects on intestinal health, including modulating the immune system and providing protection against pathogens, and many species are frequently used as probiotics. Gut bacteria acquire essential metal ions, like iron, zinc, and manganese, through the host diet and changes to the levels of these metals are often linked to alterations in microbial community composition, susceptibility to infection, and gastrointestinal diseases. Lactobacillaceae are frequently among the organisms increased or decreased in abundance due to changes in metal availability, yet many of the molecular mechanisms underlying these changes have yet to be defined. Metal requirements and metallotransporters have been studied in some species of Lactobacillaceae, but few of the mechanisms used by these bacteria to respond to metal limitation or excess have been investigated. This review provides a current overview of these mechanisms and covers how iron, zinc, and manganese impact Lactobacillaceae in the gut microbiota with an emphasis on their biochemical roles, requirements, and homeostatic mechanisms in several species.


Assuntos
Microbioma Gastrointestinal , Humanos , Animais , Lactobacillaceae , Manganês/farmacologia , Bactérias , Zinco/farmacologia , Ferro/farmacologia
6.
Int J Mol Sci ; 23(24)2022 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-36555659

RESUMO

Chronic kidney disease (CKD) represents a state of oxidative stress imbalance, which is potentially amplified by iron deficiency. Intravenous iron is considered safe and efficacious in the treatment of iron deficiency anemia, however, concerns remain regarding its potential pro-oxidant effect, leading to inflammatory and endothelial consequences. This pooled analysis of two pilot randomized controlled trials aimed to group and analyze the potential effect of high-dose intravenous iron (ferric derisomaltose, 1000 mg) on markers of oxidative stress (thiobarbituric acid reactive substance), inflammation (C-reactive protein, interleukins 6 and 10) and endothelial response (E-selectin, P-selectin) in patients with non-dialysis-dependent CKD and iron deficiency with/without anemia. Pulse wave velocity as a surrogate measure of arterial stiffness was measured. Thirty-six patients were included. No statistically significant trend was identified for any of the aforementioned markers. Stratification and comparison of data based on CKD stage did not yield statistically significant trajectories with the exception of the C-reactive protein in CKD stage 3b. These results suggest that high-dose intravenous iron does not impact measures of oxidative stress or inflammation; however, the results are not conclusive. Further research in a larger cohort is necessary to characterize the effect of intravenous iron on oxidative status and inflammation and its potential sequela in CKD.


Assuntos
Anemia Ferropriva , Insuficiência Renal Crônica , Humanos , Ferro/farmacologia , Proteína C-Reativa/metabolismo , Análise de Onda de Pulso , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo , Anemia Ferropriva/tratamento farmacológico , Compostos Férricos/efeitos adversos , Estresse Oxidativo , Inflamação/metabolismo
7.
Cells ; 11(24)2022 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-36552731

RESUMO

In scaffold-regulated bone regeneration, most three-dimensional (3D)-printed scaffolds do not provide physical stimulation to stem cells. In this study, a magnetic scaffold was fabricated using fused deposition modeling with calcium silicate (CS), iron oxide nanoparticles (Fe3O4), and poly-ε-caprolactone (PCL) as the matrix for internal magnetic sources. A static magnetic field was used as an external magnetic source. It was observed that 5% Fe3O4 provided a favorable combination of compressive strength (9.6 ± 0.9 MPa) and degradation rate (21.6 ± 1.9% for four weeks). Furthermore, the Fe3O4-containing scaffold increased in vitro bioactivity and Wharton's jelly mesenchymal stem cells' (WJMSCs) adhesion. Moreover, it was shown that the Fe3O4-containing scaffold enhanced WJMSCs' proliferation, alkaline phosphatase activity, and the osteogenic-related proteins of the scaffold. Under the synergistic effect of the static magnetic field, the CS scaffold containing Fe3O4 can not only enhance cell activity but also stimulate the simultaneous secretion of collagen I and osteocalcin. Overall, our results demonstrated that Fe3O4-containing CS/PCL scaffolds could be fabricated three dimensionally and combined with a static magnetic field to affect cell behaviors, potentially increasing the likelihood of clinical applications for bone tissue engineering.


Assuntos
Nanopartículas , Engenharia Tecidual , Engenharia Tecidual/métodos , Tecidos Suporte , Osteogênese , Poliésteres/farmacologia , Proliferação de Células , Impressão Tridimensional , Óxidos/farmacologia , Ferro/farmacologia
8.
Oxid Med Cell Longev ; 2022: 8966368, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36329803

RESUMO

Globally, osteosarcoma (OS) is the most prevalent form of primary bone cancer in children and adolescents. Traditional neoadjuvant chemotherapy regimens have reached a bottleneck; thus, OS survivors have unsatisfactory outcomes. Theaflavin-3,3'-digallate (TF3) exhibits potent anticancer properties against many human cancers. Nevertheless, the biological effects and the underlying molecular mechanism of TF3 in human OS remain unclear. The objective of this study was to investigate the effects of TF3 on human OS cell lines and mouse xenograft models. The results showed that TF3 reduced cell viability, suppressed cell proliferation, and caused G0/G1 cell cycle arrest in both MG63 and HOS cell lines in a concentration-dependent manner. TF3 also altered the homeostatic mechanisms for iron storage in the examined cell lines, resulting in an excess of labile iron. Unsurprisingly, TF3 caused oxidative stress through reduced glutathione (GSH) exhaustion, reactive oxygen species (ROS) accumulation, and the Fenton reaction, which triggered ferroptosis and apoptosis in the cells. TF3 also induced MAPK signalling pathways, including the ERK, JNK, and p38 MAPK pathways. Furthermore, oxidative stress was shown to be the primary reason for TF3-induced proliferation inhibition, programmed cell death, and MAPK pathway activation in vitro. Moreover, TF3 exhibited markedly strong antitumour efficacy in vivo in mouse models. In summary, this study demonstrates that TF3 concomitantly plays dual roles in apoptotic and ferroptotic cell death by triggering the ROS and MAPK signalling pathways in both in vitro and in vivo models.


Assuntos
Neoplasias Ósseas , Ferroptose , Osteossarcoma , Camundongos , Animais , Criança , Humanos , Adolescente , Espécies Reativas de Oxigênio/metabolismo , Xenoenxertos , Linhagem Celular Tumoral , Apoptose , Osteossarcoma/tratamento farmacológico , Proliferação de Células , Antioxidantes/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Ferro/farmacologia
9.
Tissue Cell ; 79: 101956, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36272206

RESUMO

OBJECTIVE: Ferroptosis is a novel mode of non-apoptotic cell death induced by build-up of toxic lipid peroxides (lipid-ROS) in an iron dependent manner, which is a key event in ischemia/reperfusion (I/R)-induced cardiomyocytes damages. Studies indicated that ischemic preconditioning with cardiac microvascular endothelial cells (CMECs) protected against I/R-induced cardiomyocytes damages. However, the role of hypoxia-conditioned CMECs-derived Exo (H-exo) in I/R cardiomyocytes damages remains largely unclear. Therefore, the objective of this study was to explore the role and underlying mechanisms of H-exo in hypoxia/reoxygenation(H/R)-induced H9C2 cells damages. METHODS: The rat CMECs were subjected to hypoxia or normoxia culture and Exo was subsequently collected and identified. H-exo or normoxia-conditioned CMECs-derived Exo (N-exo) were administered to H9C2 cells with H/R. To evaluate the therapeutic effect of H-exo and H-exo on H/R-induced H9C2 cells damages, cell proliferation was detected by CCK-8 assay and Edu staining, and ferroptosis process were evaluated by iron ion concentration, lipid reactive oxygen species (ROS) level, malondialdehyde (MDA) level, glutathione peroxidase (GSH-Px) level, and the protein expression of ferroptosis markers. Mechanically, we utilized the RT-qPCR to identify the expression of candidate miR-210-3p in N-exo and H-exo. Bioinformatics combined with dual luciferase reporter assay disclosed the downstream molecular mechanism of miR-210-3p. RESULTS: The results indicated that both H-exo and N-exo significantly facilitated cell proliferation, increased GSH-Px levels and ferroptosis marker (GPX4) protein levels, and reduced iron ion concentration, lipid ROS level, MDA levels and ferroptosis markers (ACSL4 and PTGS2) protein levels in H/R-treated H9C2 cells. More importantly, the therapeutic effect of H-exo was significantly better than that of N-exo. Mechanistically, the results of RT-qPCR revealed significant enrichment of miR-210-3p in H-exo compared with N-exo. The miR-210-3p delivered by H-exo inhibited TFR expression by directly interacting with TFR mRNA, resulting in the promotion of cell proliferation and the attenuation of cell ferroptosis in H/R-treated H9C2 cells. CONCLUSION: All these data demonstrated that H-exo derived miR-210-3p facilitated the proliferation of myocardial cells in H/R-treated H9C2 cells by suppressing TFR-mediated ferroptosis, which provided new methods to treat H/R-induced myocardial injury.


Assuntos
Ferroptose , MicroRNAs , Ratos , Animais , Miócitos Cardíacos/metabolismo , Ferroptose/genética , Células Endoteliais/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Apoptose , MicroRNAs/metabolismo , Hipóxia/metabolismo , Receptores da Transferrina/genética , Receptores da Transferrina/metabolismo , Ferro/metabolismo , Ferro/farmacologia , Lipídeos/farmacologia
10.
Int J Mol Sci ; 23(20)2022 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-36293381

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible and pathogenic coronavirus that has caused a 'coronavirus disease 2019' (COVID-19) pandemic in multiple waves, which threatens human health and public safety. During this pandemic, some patients with COVID-19 acquired secondary infections, such as mucormycosis, also known as black fungus disease. Mucormycosis is a serious, acute, and deadly fungal infection caused by Mucorales-related fungal species, and it spreads rapidly. Hence, prompt diagnosis and treatment are necessary to avoid high mortality and morbidity rates. Major risk factors for this disease include uncontrolled diabetes mellitus and immunosuppression that can also facilitate increases in mucormycosis infections. The extensive use of steroids to prevent the worsening of COVID-19 can lead to black fungus infection. Generally, antifungal agents dedicated to medical applications must be biocompatible, non-toxic, easily soluble, efficient, and hypoallergenic. They should also provide long-term protection against fungal growth. COVID-19-related black fungus infection causes a severe increase in fatalities. Therefore, there is a strong need for the development of novel and efficient antimicrobial agents. Recently, nanoparticle-containing products available in the market have been used as antimicrobial agents to prevent bacterial growth, but little is known about their efficacy with respect to preventing fungal growth, especially black fungus. The present review focuses on the effect of various types of metal nanoparticles, specifically those containing silver, zinc oxide, gold, copper, titanium, magnetic, iron, and carbon, on the growth of various types of fungi. We particularly focused on how these nanoparticles can impact the growth of black fungus. We also discussed black fungus co-infection in the context of the global COVID-19 outbreak, and management and guidelines to help control COVID-19-associated black fungus infection. Finally, this review aimed to elucidate the relationship between COVID-19 and mucormycosis.


Assuntos
Mucorales , Mucormicose , Nanopartículas , Óxido de Zinco , Humanos , SARS-CoV-2 , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Mucormicose/tratamento farmacológico , Mucormicose/epidemiologia , Mucormicose/microbiologia , Prata/farmacologia , Óxido de Zinco/farmacologia , Cobre/farmacologia , Titânio/farmacologia , Ferro/farmacologia , Ouro/farmacologia , Carbono/farmacologia
11.
J Agric Food Chem ; 70(42): 13499-13509, 2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36223430

RESUMO

Increasingly intensive agricultural practices are leading not only to herbicide contamination but also to nutritional stress on nontarget plants. This study evaluated the role of heme oxygenase-1 (HO-1) in the dual stress response of herbicide dichlorprop and micronutrient Fe in Arabidopsis thaliana. Our results revealed that co-treatment with 20 µM zinc protoporphyrin (a specific inhibitor of HO-1) reduced the activity of HO-1 by 21.6%, Fe2+ content by 19.8%, and MDA content by 20.0%, reducing abnormal iron aggregation and oxidative stress in response to the herbicide compared to treatment with (R)-dichloroprop alone, which has herbicidal activity. Thus, free Fe2+ released from HO-1 mediated dichlorprop-induced oxidative stress in the Fenton reaction and affected aberrant Fe aggregation, which also had an enantioselective effect. This study contributes to an in-depth understanding of the toxicity mechanism of herbicides under nutrient stresses, thus providing new strategies to control the environmental risks of herbicides.


Assuntos
Arabidopsis , Herbicidas , Oligoelementos , Herbicidas/toxicidade , Arabidopsis/metabolismo , Heme Oxigenase-1/metabolismo , Micronutrientes , Estresse Oxidativo , Ferro/farmacologia , Heme Oxigenase (Desciclizante)/farmacologia
12.
Arch Microbiol ; 204(11): 667, 2022 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-36217038

RESUMO

Salmonella is one among the most versatile and resilient enteric pathogens that is known to have developed various survival strategies within the host system. The ability of the bacteria to circumvent the physiological parameters as well as dodge the antimicrobial stress environment within the host is one of the most crucial steps in establishing an infection. With an alarming rise in multi-drug resistant serovars of non-typhoidal Salmonella and lack of vaccine for combatting the infections, behaviour of the bacteria in the presence of host physiological conditions (NaCl, high and low iron) and antibiotics will help in understanding the survival strategies as well as mechanisms of resistance. Two multi-drug resistant and two sensitive serovars of Salmonella Weltevreden and Salmonella Newport isolated from poultry and seafood were used for growth kinetics and virulence gene expression study. The results obtained revealed that despite similar resistance pattern, effect of individual class of antibiotics on the growth of serovars varied. On the contrary, no significant difference was observed in growth pattern on exposure to these in vitro experimental conditions. Nevertheless, coupling these conditions with antibiotics drastically reduced the minimum inhibitory concentration (MIC) of antibiotics in resistant strains. A first of its kind study that draws attention on the significant effect of antibiotics and physiological conditions on MIC between resistant and sensitive non-typhoidal Salmonella serovars and expression of virulence genes from Salmonella pathogenicity island (SPI) 1 and 2 (invA, hilC, fliC2, sseA and ssrB).


Assuntos
Antibacterianos , Cloreto de Sódio , Antibacterianos/farmacologia , Expressão Gênica , Ferro/farmacologia , Quelantes de Ferro/farmacologia , Salmonella , Cloreto de Sódio/farmacologia , Virulência/genética
13.
Ecotoxicol Environ Saf ; 246: 114133, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36201916

RESUMO

This study prepared surface-modified biochar, including acid washing biochar (HBC) and biochar supported with nanoscale zero-valent iron (nZVI-HBC). The surface-modified biochar was added to sulfamethoxazole (SMX)-contaminated soil with and without earthworms to examine the effects of surface-modified biochar and/or earthworms (Eisenia fetida) on the levels of SMX and its relevant genes (sul1, sul2, and intI1) in the soil. Additionally, the joint toxicity of these exogenous substances on earthworms was investigated. The results showed that although earthworms significantly enhanced the dissipation of SMX in the soils with and without HBC, this effect was not observed in the soil with nZVI-HBC. Among all treatments, nZVI-HBC most effectively accelerated SMX dissipation in the soil, regardless of coexisting earthworms. However, the presence of earthworms significantly increased the total relative abundances of sul1, sul2, and intI1 in the soil. A reasonable explanation for this is the shift in the bacterial community composition rather than the residual level of SMX. When earthworms coexisted, the richness of Proteobacteria evidently increased, which was the main host of the above genes. Both HBC and nZVI-HBC decreased these genes in the soil with earthworms, which was mainly due to the decrease in host genera from Proteobacteria, Actinobacteria, and Gemmatimonadetes. Although there was toxicity of single-surface-modified biochar or SMX on earthworms, the synergistic interaction of surface-modified biochar and SMX resulted in the most serious histopathological changes in earthworms and their highest superoxide dismutase activity.


Assuntos
Oligoquetos , Poluentes do Solo , Animais , Ferro/farmacologia , Sulfametoxazol/toxicidade , Poluentes do Solo/análise , Carvão Vegetal/farmacologia , Solo
14.
An Acad Bras Cienc ; 94(suppl 3): e20211098, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36197361

RESUMO

Iron is essential to plant development. However, its excess can provoke an increase in reactive oxygen species and oxidative stress in plants. The objective of this work was to verify the effects of high concentrations of iron on the oxidative stress of seeds and young plants of Cecropia hololeuca and Carica papaya. The species were submitted to concentrations of 0.045, 4 and 8mM of iron in the form of ferrous sulfate and FeEDTA. The experiments of germination and initial growth took place in a growth chamber, with temperature of 25ºC and 12h photoperiod. We performed the lipid peroxidation test by extraction and quantification of malonaldehyde and hydrogen peroxide. The application of iron did not cause a significant elevation in the contents of malonaldehyde and hydrogen peroxide in the germination of C. hololeuca and C. papaya. In the young plants, the hydrogen peroxide did not change in any of the treatments. However, it was possible to observe an expressive increase in malonaldehyde concentration in both species when exposed to FeEDTA 4 to 8mM. The results indicate a sensibility of C. hololeuca and C. papaya to high iron levels, amplifying the oxidative stress process that can harm their growth and initial development.


Assuntos
Carica , Peróxido de Hidrogênio/farmacologia , Ferro/farmacologia , Malondialdeído , Estresse Oxidativo , Espécies Reativas de Oxigênio
15.
Molecules ; 27(20)2022 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-36296439

RESUMO

Leishmaniasis is a vector-borne disease caused by protozoal Leishmania parasites. Previous studies have shown that endoperoxides (EP) can selectively kill Leishmania in host cells. Therefore, we studied in this work a set of new anthracene-derived EP (AcEP) together with their non-endoperoxidic analogs in model systems of Leishmania tarentolae promastigotes (LtP) and J774 macrophages for their antileishmanial activity and selectivity. The mechanism of effective compounds was explored by studying their reaction with iron (II) in chemical systems and in Leishmania. The correlation of structural parameters with activity demonstrated that in this compound set, active compounds had a LogPOW larger than 3.5 and a polar surface area smaller than 100 Å2. The most effective compounds (IC50 in LtP < 2 µM) with the highest selectivity (SI > 30) were pyridyl-/tert-butyl-substituted AcEP. Interestingly, also their analogs demonstrated activity and selectivity. In mechanistic studies, it was shown that EP were activated by iron in chemical systems and in LtP due to their EP group. However, the molecular structure beyond the EP group significantly contributed to their differential mitochondrial inhibition in Leishmania. The identified compound pairs are a good starting point for subsequent experiments in pathogenic Leishmania in vitro and in animal models.


Assuntos
Antiprotozoários , Leishmania , Animais , Antiprotozoários/farmacologia , Relação Estrutura-Atividade , Antracenos/farmacologia , Ferro/farmacologia
16.
Int J Mol Sci ; 23(19)2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-36232424

RESUMO

A. hydrophila is an important pathogen that mainly harms aquatic animals and has exhibited resistance to a variety of antibiotics. Here, to seek an effective alternative for antibiotics, the effects of umbelliferone (UM) at sub-MICs on A. hydrophila virulence factors and the quorum-sensing system were studied. Subsequently, RNA sequencing was employed to explore the potential mechanisms for the antivirulence activity of umbelliferone. Meanwhile, the protective effect of umbelliferone on grass carp infected with A. hydrophila was studied in vivo. Our results indicated that umbelliferone could significantly inhibit A. hydrophila virulence such as hemolysis, biofilm formation, swimming and swarming motility, and their quorum-sensing signals AHL and AI-2. Transcriptomic analysis showed that umbelliferone downregulated expression levels of genes related to exotoxin, the secretory system (T2SS and T6SS), iron uptake, etc. Animal studies demonstrated that umbelliferone could significantly improve the survival of grass carps infected with A. hydrophila, reduce the bacterial load in the various tissues, and ameliorate cardiac, splenic, and hepatopancreas injury. Collectively, umbelliferone can reduce the pathogenicity of A. hydrophila and is a potential drug for treating A. hydrophila infection.


Assuntos
Carpas , Doenças dos Peixes , Infecções por Bactérias Gram-Negativas , Aeromonas hydrophila , Animais , Antibacterianos/farmacologia , Exotoxinas/farmacologia , Doenças dos Peixes/tratamento farmacológico , Doenças dos Peixes/genética , Doenças dos Peixes/prevenção & controle , Infecções por Bactérias Gram-Negativas/microbiologia , Ferro/farmacologia , Umbeliferonas/farmacologia , Fatores de Virulência/genética , Fatores de Virulência/farmacologia
17.
Rev Esp Quimioter ; 35 Suppl 2: 16-19, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36193980

RESUMO

Gram-negative bacilli are intrinsically resistant to many antibiotics due to the low permeability of their outer membrane. The most effective strategy to solve this problem has been the design of antibiotics that cross the membrane using specific transport systems. This is the case of cefiderocol, which, unlike cefepime or ceftazidime, has a chlorocatechol group at the end of the C-3 side chain. This group is recognized by transporters located in the outer membrane that allow cefiderocol to accumulate in the periplasmic space. Furthermore, cefiderocol is not a substrate for efflux pumps and the configuration of the side chains at C-7 and in particular at C-3 confer it a high stability against hydrolysis by most beta-lactamases of clinical interest including class A (KPC, BLEEs), C (ampC) or D (OXA-48) serine beta-lactamases and metallo-betalactamases (NDM, VIM. IMP). In order to better understand the mechanism of action of cefiderocol, the importance of iron in bacterial metabolism and the competition for iron between bacteria and host are reviewed.The indiscriminate and massive antibiotic use in the clinical practice and in agriculture or cattle during the past few decades has produced a serious world health problem that entails high morbidity and mortality: the antibiotic multi-drug resistance. In 2017 and 2019, the World Health Organization published a list of urgent threats and priorities in the context of drug resistance, which only included Gram-negative bacteria and specially focused on carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa, as well as carbapenem and third generation cephalosporin-resistant Enterobacteriaceae. This scenario emphasizes the need of developing and testing new antibiotics from different families, such as new beta-lactams, highlighting cefiderocol and its original mechanism of action; new beta-lactamase inhibitors, with vaborbactam or relebactam among others; new quinolones such as delafloxacin, and also omadacycline or eravacycline, as members of the tetracycline family. The present work reviews the importance and impact of Gram-negative bacterial infections and their resistance mechanisms, and analyzes the current therapeutic paradigm as well as the role of new antibiotics with a promising future in the era of multi and pan-drug resistance.


Assuntos
Quinolonas , Inibidores de beta-Lactamases , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Carbapenêmicos/farmacologia , Bovinos , Cefepima/farmacologia , Ceftazidima , Cefalosporinas/farmacologia , Cefalosporinas/uso terapêutico , Bactérias Gram-Negativas , Inosina Monofosfato/farmacologia , Ferro/farmacologia , Quinolonas/farmacologia , Serina/farmacologia , Tetraciclinas/farmacologia , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/metabolismo
18.
Rev Esp Quimioter ; 35 Suppl 2: 20-27, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36193981

RESUMO

Cefiderocol, a siderophore catechol cephalosporin, recently introduced in the market has been developed to enhance the in vitro activity of extended spectrum cephalosporins and to avoid resistance mechanisms affecting cephalosporins and carbapenems. The in vitro study of cefiderocol in the laboratory requires iron depleted media when MIC values are determined by broth microdilution. Disk diffusion presents good correlation with MIC values. In surveillance studies and in clinical trials it has been demonstrated excellent activity against Gram-negatives, including carbapenemase producers and non-fermenters such as Pseudomonas aeruginosa, Acinetobacter baumannii and Stenotrophomonas maltophilia. Few cefiderocol resistant isolates have been found in surveillance studies. Resistance mechanisms are not directly associated with porin deficiency and or efflux pumps. On the contrary, they are related with gene mutations affecting iron transporters, AmpC mutations in the omega loop and with certain beta-lactamases such us KPC-variants determining also ceftazidime-avibactam resistance, certain infrequent extended-spectrum betalactamases (PER, BEL) and metallo-beta-lactamases (certain NDM variants and SPM enzyme).


Assuntos
Farmacorresistência Bacteriana Múltipla , Sideróforos , Antibacterianos/farmacologia , Carbapenêmicos/farmacologia , Catecóis/farmacologia , Cefalosporinas/farmacologia , Farmacorresistência Bacteriana Múltipla/genética , Humanos , Ferro/farmacologia , Testes de Sensibilidade Microbiana , Porinas/farmacologia , Pseudomonas aeruginosa/genética , Sideróforos/farmacologia , beta-Lactamases/genética , beta-Lactamases/metabolismo
19.
Mol Med ; 28(1): 121, 2022 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-36192693

RESUMO

BACKGROUND: Stent implantation-induced neointima formation is a dominant culprit in coronary artery disease treatment failure after percutaneous coronary intervention. Ferroptosis, an iron-dependent regulated cell death, has been associated with various cardiovascular diseases. However, the effect of ferroptosis on neointima formation remains unclear. METHODS: The mouse common right carotid arteries were ligated for 16 or 30 days, and ligated tissues were collected for further analyses. Primary rat vascular smooth muscle cells (VSMCs) were isolated from the media of aortas of Sprague-Dawley (SD) rats and used for in vitro cell culture experiments. RESULTS: Ferroptosis was positively associated with neointima formation. In vivo, RAS-selective lethal 3 (RSL3), a ferroptosis activator, aggravated carotid artery ligation-induced neointima formation and promoted VSMC phenotypic conversion. In contrast, a ferroptosis inhibitor, ferrostatin-1 (Fer-1), showed the opposite effects in mice. In vitro, RSL3 promoted rat VSMC phenotypic switching from a contractile to a synthetic phenotype, evidenced by increased contractile markers (smooth muscle myosin heavy chain and calponin 1), and decreased synthetic marker osteopontin. The induction of ferroptosis by RSL3 was confirmed by the increased expression level of ferroptosis-associated gene prostaglandin-endoperoxide synthase 2 (Ptgs2). The effect of RSL3 on rat VSMC phenotypic switching was abolished by Fer-1. Moreover, N-acetyl-L-cysteine (NAC), the reactive oxygen species inhibitor, counteracted the effect of RSL3 on the phenotypic conversion of rat VSMCs. CONCLUSIONS: Ferroptosis induces VSMC phenotypic switching and accelerates ligation-induced neointimal hyperplasia in mice. Our findings suggest inhibition of ferroptosis as an attractive strategy for limiting vascular restenosis.


Assuntos
Ferroptose , Neointima , Acetilcisteína/farmacologia , Animais , Movimento Celular , Proliferação de Células , Células Cultivadas , Ciclo-Oxigenase 2/metabolismo , Ciclo-Oxigenase 2/farmacologia , Modelos Animais de Doenças , Hiperplasia/metabolismo , Ferro/metabolismo , Ferro/farmacologia , Camundongos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Osteopontina/metabolismo , Osteopontina/farmacologia , Fenótipo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Miosinas de Músculo Liso/metabolismo
20.
Oxid Med Cell Longev ; 2022: 3472443, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36160714

RESUMO

Lumbar spinal stenosis (LSS) is a common degenerative spinal condition in older individuals that causes impaired walking and other disabilities due to severe lower back and leg pain. Ligamentum flavum hypertrophy is a major LSS cause that may result from oxidative stress caused by degenerative cascades, including imbalanced iron homeostasis that leads to excessive reactive oxygen species production. We investigated the effects of Harpagophytum procumbens (HP) on iron-induced oxidative stress associated with LSS pathophysiology. Primary spinal cord neuron cultures were incubated in FeSO4-containing medium, followed by addition of 50, 100, or 200 µg/mL HP. Cell viability was assessed by CCK-8 and live/dead cell assays and by propidium iodide-live imaging. In an in vivo rat model of LSS, HP were administered at 100, 200, and 400 mg/kg, and disease progression was monitored for up to 3 weeks. We investigated the in vitro and in vivo effects of HP on iron-induced neurotoxicity by immunochemistry, real-time PCR, and flow cytometry. HP exerted neuroprotective effects and enhanced neurite outgrowths of iron-injured rat primary spinal cord neurons in vitro. HP treatment significantly reduced necrotic cell death and improved cells' antioxidative capacity via the NRF2 signaling pathway in iron-treated neurons. At 1 week after HP administration in LSS rats, the inflammatory response and oxidative stress markers were substantially reduced through regulation of excess iron accumulation. Iron that accumulated in the spinal cord underneath the implanted silicone was also regulated by HP administration via NRF2 signaling pathway activation. HP-treated LSS rats showed gradually reduced mechanical allodynia and amelioration of impaired behavior for 3 weeks. We demonstrated that HP administration can maintain iron homeostasis within neurons via activation of NRF2 signaling and can consequently facilitate functional recovery by regulating iron-induced oxidative stress. This fundamentally new strategy holds promise for LSS treatment.


Assuntos
Harpagophytum , Sobrecarga de Ferro , Fármacos Neuroprotetores , Estenose Espinal , Animais , Fator de Transcrição de Proteínas de Ligação GA , Ferro/farmacologia , Sobrecarga de Ferro/complicações , Sobrecarga de Ferro/tratamento farmacológico , Fator 2 Relacionado a NF-E2/farmacologia , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo , Propídio/farmacologia , Ratos , Espécies Reativas de Oxigênio/farmacologia , Transdução de Sinais , Silicones/farmacologia , Sincalida/farmacologia , Estenose Espinal/complicações
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