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1.
Rev Port Cardiol ; 41(10): 813-819, 2022 Oct.
Artigo em Inglês, Português | MEDLINE | ID: mdl-36210587

RESUMO

OBJECTIVES: Hyperhomocysteinemia (HHcy) can induce vascular inflammatory and oxidative damage and accelerate intimal hyperplasia. This study investigated the protective effect of pirfenidone (PFD) on the recovery process of injured endothelial arteries during HHcy. MATERIALS AND METHODS: Thirty rabbits were randomly separated into three groups: A control group (n=10, standard rabbit chow), a model group (n=10, control diet plus 30 g methionine/kg food), and a PFD group (n=10, model diet plus oral administration of 90 mg/day of PFD). After 14 weeks of arterial injury, histopathological changes were determined. Plasma homocysteine (Hcy) concentrations, lipid profiles and oxidant and antioxidant status were evaluated. Macrophage infiltration was assessed using immunohistochemical staining. RESULTS: PFD supplementation decreased macrophage infiltration of iliac artery significantly without changes in blood lipids and Hcy concentrations. Compared with the model group, PFD restored superoxide dismutase and glutathione peroxidase activities and reduced malondialdehyde and reactive oxygen species levels. A high-methionine diet significantly increased neointimal area and the ratio between neointimal and media area. Systemic administration of PFD inhibited neointimal formation. CONCLUSIONS: PFD can partly alleviate intimal hyperplasia by inhibiting inflammatory and oxidative stress response induced by HHcy during endothelial injury. It may be a potential therapeutic agent for the prevention and treatment of endothelial injury-associated diseases such as atherosclerosis.


Assuntos
Hiper-Homocisteinemia , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Glutationa Peroxidase/farmacologia , Glutationa Peroxidase/uso terapêutico , Homocisteína/farmacologia , Homocisteína/uso terapêutico , Hiper-Homocisteinemia/complicações , Hiper-Homocisteinemia/tratamento farmacológico , Hiper-Homocisteinemia/patologia , Hiperplasia/patologia , Lipídeos , Malondialdeído/farmacologia , Metionina/farmacologia , Metionina/uso terapêutico , Oxidantes/farmacologia , Oxidantes/uso terapêutico , Piridonas , Coelhos , Espécies Reativas de Oxigênio/farmacologia , Espécies Reativas de Oxigênio/uso terapêutico , Superóxido Dismutase/farmacologia , Superóxido Dismutase/uso terapêutico , Túnica Íntima/patologia
2.
Acta Neurobiol Exp (Wars) ; 82(3): 254-262, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36214708

RESUMO

Cobalt is a trace element that increases lipid peroxidation and malondialdehyde levels and reduces the antioxidant defense mechanisms of nerve cells. High levels of cobalt exposure may cause peripheral neuropathy, but the mechanism behind this has not yet been elucidated. Taxifolin is a flavonoid whose antioxidant and anti­inflammatory properties are well­known. We aimed to investigate the effect of taxifolin on cobalt­induced oxidative sciatic nerve damage. Eighteen albino male Wistar rats were assigned to three groups: Control, Cobalt, and Taxifolin + Cobalt groups. Total oxidant and total antioxidant status and levels of malondialdehyde, total glutathione, and superoxide dismutase were measured to determine the effect of taxifolin on cobalt­induced sciatic nerve injury. The following statistically significant effect of taxifolin was observed: It prevented cobalt­induced oxidative sciatic nerve damage by reducing malondialdehyde levels and total oxidant status and increasing total antioxidant status, total glutathione levels, and superoxide dismutase levels. In a histopathological analysis, we observed similar findings in Control and Taxifolin + Cobalt groups. We determined that taxifolin is effective in preventing cobalt­induced oxidative damage in sciatic nerve injury.


Assuntos
Antioxidantes , Oligoelementos , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Cobalto/toxicidade , Glutationa/metabolismo , Malondialdeído , Oxidantes/farmacologia , Estresse Oxidativo/fisiologia , Quercetina/análogos & derivados , Quercetina/farmacologia , Quercetina/uso terapêutico , Ratos , Ratos Wistar , Nervo Isquiático/metabolismo , Nervo Isquiático/patologia , Superóxido Dismutase/metabolismo , Oligoelementos/farmacologia
3.
Harmful Algae ; 118: 102311, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36195425

RESUMO

Numerous products and techniques are used to combat harmful cyanobacterial blooms in lakes. In this study, we tested nine products, the phosphate binders Phoslock® and Aqual-PTM, the coagulant chitosan, the phosphorus binder and coagulant aluminum salts (aluminum sulphate and sodium aluminate), the copper-based algicides SeClear, Captain® XTR and CuSO4·5H2O, the antibiotic Streptomycin and the oxidant hydrogen peroxide (H2O2) on their efficiency to manage the cyanobacterium Microcystis aeruginosa (M. aeruginosa). To this end, 7 days of laboratory experiments were conducted and effects were determined on chlorophyll-a, photosystem II efficiency (PSII), soluble reactive phosphorus (SRP) and intracellular and extracellular microcystin (MC) concentrations. The algicides, chitosan and H2O2 were the most powerful in reducing cyanobacteria biomass. Biomass reductions compared to the controls yielded: Chitosan (99.8%) > Hydrogen peroxide (99.6%) > Captain XTR (98.2%) > SeClear (98.1%) > CuSO4·5H2O (97.8%) > Streptomycin (86.6%) > Phoslock® (42.6%) > Aqual-PTM (28.4%) > alum (5.5%). Compounds that caused the largest reductions in biomass also strongly lowered photosystem II efficiency, while the other compounds (Phoslock®, Aqual-PTM, aluminum salts) had no effect on PSII, but strongly reduced SRP. Intracellular MC concentration followed the biomass patterns, extracellular MC was generally lower at higher doses of algicides, chitosan and H2O2 after one week. Recovery of PSII was observed in most algicides and chitosan, but not at the highest doses of SeClear and in all streptomycin treatments. Our results revealed that M. aeruginosa can be killed rapidly using several compounds, that in some treatments already signs of recovery occurred within one week. P fixatives are efficient in reducing SRP, and thus acting via resource suppression, which potentially may provide an addition to fast-acting algicides that kill most of the cells, but allow rapid regrowth as sufficient nutrients remain.


Assuntos
Quitosana , Cianobactérias , Herbicidas , Microcystis , Alumínio/farmacologia , Antibacterianos/farmacologia , Quitosana/farmacologia , Clorofila , Cobre/farmacologia , Fixadores/farmacologia , Herbicidas/farmacologia , Peróxido de Hidrogênio , Microcistinas/farmacologia , Oxidantes/farmacologia , Fosfatos , Fósforo/farmacologia , Complexo de Proteína do Fotossistema II , Sais/farmacologia , Estreptomicina/farmacologia , Sulfatos/farmacologia
4.
Physiol Rep ; 10(20): e15507, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36305701

RESUMO

Acute kidney injury (AKI) is a common event, occurring in ~5% and ~35% of hospitalized and ICU patients, respectively. The development of AKI portends an increased risk of morbidity, mortality, prolonged hospitalization, and subsequent development of chronic kidney disease (CKD). Given these facts, a multitude of experimental studies have addressed potential methods for inducing AKI prevention in high-risk patients. However, successful clinical translation of promising experimental data has remained elusive. Over the past decade, our laboratory has focused on developing a method for safely triggering AKI protection by inducing "kidney preconditioning" in mice by the intravenous administration of a combination of Fe sucrose (FeS) + tin protoporphyrin (SnPP). These agents induce mild, but short lived, 'oxidant stress' which synergistically activate a number of kidney 'self-defense' pathways (e.g., Nrf2, ferritin, IL-10). Within 18-24 h of Fe/SnPP administration, marked protection against diverse forms of experimental toxic and ischemic AKI results. FeS/SnPP-mediated reductions in kidney injury can also indirectly decrease injury in other organs by mitigating the so called "organ cross talk" phenomenon. Given these promising experimental data, three phase 1b clinical trials were undertaken in healthy subjects and patients with stage 3 or 4 CKD. These studies demonstrated that FeS/SnPP were well tolerated and that they up-regulated the cytoprotective Nrf2, ferritin, and IL-10 pathways. Two subsequent phase 2 trials, conducted in patients undergoing 'on-pump' cardiovascular surgery or in patients hospitalized with COVID 19, confirmed FeS/SnPP safety. Furthermore, interim data analyses revealed statistically significant improvements in several clinical parameters. The goals of this review are to: (i) briefly discuss the historical background of renal "preconditioning"; (ii) present the experimental data that support the concept of FeS/SnPP- induced organ protection; and (iii) discuss the initial results of clinical trials that suggest the potential clinical utility of an 'oxidant preconditioning' strategy.


Assuntos
Injúria Renal Aguda , COVID-19 , Insuficiência Renal Crônica , Camundongos , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Interleucina-10/metabolismo , Oxidantes/farmacologia , Rim/metabolismo , Injúria Renal Aguda/prevenção & controle , Injúria Renal Aguda/metabolismo , Insuficiência Renal Crônica/prevenção & controle , Insuficiência Renal Crônica/metabolismo , Ferritinas
5.
Cells ; 11(20)2022 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-36291178

RESUMO

The binding of SARS-CoV-2 spikes to the cell receptor angiotensin-converting enzyme 2 (ACE2) is a crucial target both in the prevention and in the therapy of COVID-19. We explored the involvement of oxidoreductive mechanisms by investigating the effects of oxidants and antioxidants on virus uptake by ACE2-expressing cells of human origin (ACE2-HEK293). The cell uptake of pseudoviruses carrying the envelope of either Delta or Omicron variants of SARS-CoV-2 was evaluated by means of a cytofluorimetric approach. The thiol N-acetyl-L-cysteine (NAC) inhibited the uptake of both variants in a reproducible and dose-dependent fashion. Ascorbic acid showed modest effects. In contrast, neither hydrogen peroxide (H2O2) nor a system-generating reactive oxygen species (ROS), which play an important role in the intracellular alterations produced by SARS-CoV-2, were able to affect the ability of either Delta or Omicron SARS-CoV-2 pseudoviruses to be internalized into ACE2-expressing cells. In addition, neither H2O2 nor the ROS generating system interfered with the ability of NAC to inhibit that mechanism. Moreover, based on previous studies, a preventive pharmacological approach with NAC would have the advantage of decreasing the risk of developing COVID-19, irrespective of its variants, and at the same time other respiratory viral infections and associated comorbidities.


Assuntos
Enzima de Conversão de Angiotensina 2 , COVID-19 , Humanos , SARS-CoV-2 , Acetilcisteína/farmacologia , COVID-19/tratamento farmacológico , Peróxido de Hidrogênio/farmacologia , Espécies Reativas de Oxigênio , Antioxidantes/farmacologia , Células HEK293 , Peptidil Dipeptidase A/metabolismo , Ácido Ascórbico/farmacologia , Oxidantes/farmacologia , Compostos de Sulfidrila/farmacologia
6.
Sci Rep ; 12(1): 16615, 2022 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-36198753

RESUMO

In this study, heavy metal pollution in the Pazarsuyu stream of Giresun province and the protective role of lycopene against the toxicity caused by this pollution were investigated using the Allium test. Germination percentage, root length and weight gain as physiological markers of toxicity; mitotic index (MI), micronucleus (MN) and chromosomal aberrations (CAs) as genetic markers of toxicity; malondialdehyde (MDA) level, superoxide dismutase (SOD) and catalase (CAT) activities as biochemical markers of toxicity, and meristematic cell damages were used as anatomical markers. For this aim Allium cepa L. bulbs were divided into six groups and germinated for 72 h with 215 mg/L and 430 mg/L doses of lycopene, tap water and stream water. Heavy metals pollution was analyzed with ICP-MS and Fe > Sr > Ba > Be > Mo > Li were determined according to the rate of presence in the water samples of Pazarsuyu. As a result, germination-related parameters and meristematic cell proliferation of bulbs germinated with Pazarsuyu water samples decreased significantly. Germination percentage, root length and weight gain of the group treated with Pazarsuyu water samples were decreased 50%, 73% and 68%, respectively compared to control. In addition, MN and CAs frequencies, indicating the genotoxic effects, were increased and significant abnormalities were detected in MDA, SOD and CAT levels, which indicate the deterioration of antioxidant/oxidant balance. CA observed with high frequency was also confirmed by DNA fragmentation determined by the Comet test. Stream water application promoted anatomical damages such as epidermis and cortex cell damage, accumulation of some substances in cortex cells, flattened cell nucleus and non-apparent appearance of conduction tissue in root tip meristem cells. All these abnormalities observed in A. cepa root tip cells were associated with the presence of heavy metals in the water samples. Simultaneous application of lycopene with stream water reduced the effects of heavy metals and resulted in a dose-dependent improvement in all parameters studied. Lycopene application showed a protective role by providing an increase in germination parameters and MI, decrease in MN and CAs frequencies, and improvements in MDA, SOD and CAT activities. As a result, heavy metals detected in the water samples of Pazarsuyu stream caused multiple toxicities in the bio-indicator plant, and lycopene reduced this toxicity and recorded a protective role.


Assuntos
Antioxidantes , Metais Pesados , Antioxidantes/farmacologia , Catalase/farmacologia , Marcadores Genéticos , Licopeno/farmacologia , Malondialdeído , Metais Pesados/toxicidade , Cebolas , Oxidantes/farmacologia , Raízes de Plantas , Superóxido Dismutase/farmacologia , Água/farmacologia , Aumento de Peso
7.
Int J Mol Sci ; 23(18)2022 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-36142492

RESUMO

Nano- and microparticles enter the body through the respiratory airways and the digestive system, or form as biominerals in the gall bladder, salivary glands, urinary bladder, kidney, or diabetic pancreas. Calcium, magnesium, and phosphate ions can precipitate from biological fluids in the presence of mucin as hybrid nanoparticles. Calcium carbonate nanocrystallites also trap mucin and are assembled into hybrid microparticles. Both mucin and calcium carbonate polymorphs (calcite, aragonite, and vaterite) are known to be components of such biominerals as gallstones which provoke inflammatory reactions. Our study was aimed at evaluation of neutrophil activation by hybrid vaterite-mucin microparticles (CCM). Vaterite microparticles (CC) and CCM were prepared under standard conditions. The diameter of CC and CCM was 3.3 ± 0.8 µm and 5.8 ± 0.7 µm, with ƺ-potentials of -1 ± 1 mV and -7 ± 1 mV, respectively. CC microparticles injured less than 2% of erythrocytes in 2 h at 1.5 mg mL-1, and no hemolysis was detected with CCM; this let us exclude direct damage of cellular membranes by microparticles. Activation of neutrophils was analyzed by luminol- and lucigenin-dependent chemiluminescence (Lum-CL and Luc-CL), by cytokine gene expression (IL-6, IL-8, IL-10) and release (IL-1ß, IL-6, IL-8, IL-10, TNF-α), and by light microscopy of stained smears. There was a 10-fold and higher increase in the amplitude of Lum-CL and Luc-CL after stimulation of neutrophils with CCM relative to CC. Adsorption of mucin onto prefabricated CC microparticles also contributed to activation of neutrophil CL, unlike mucin adsorption onto yeast cell walls (zymosan); adsorbed mucin partially suppressed zymosan-stimulated production of oxidants by neutrophils. Preliminary treatment of CCM with 0.1-10 mM NaOCl decreased subsequent activation of Lum-CL and Luc-CL of neutrophils depending on the used NaOCl concentration, presumably because of the surface mucin oxidation. Based on the results of ELISA, incubation of neutrophils with CCM downregulated IL-6 production but upregulated that of IL-8. IL-6 and IL-8 gene expression in neutrophils was not affected by CC or CCM according to RT2-PCR data, which means that post-translational regulation was involved. Light microscopy revealed adhesion of CC and CCM microparticles onto the neutrophils; CCM increased neutrophil aggregation with a tendency to form neutrophil extracellular traps (NETs). We came to the conclusion that the main features of neutrophil reaction to mucin-vaterite hybrid microparticles are increased oxidant production, cell aggregation, and NET-like structure formation, but without significant cytokine release (except for IL-8). This effect of mucin is not anion-specific since particles of powdered kidney stone (mainly calcium oxalate) in the present study or calcium phosphate nanowires in our previous report also activated Lum-CL and Luc-CL response of neutrophils after mucin sorption.


Assuntos
Luminol , Neutrófilos , Cálcio/metabolismo , Carbonato de Cálcio/farmacologia , Oxalato de Cálcio/metabolismo , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Íons/metabolismo , Luminol/química , Magnésio/metabolismo , Mucinas/metabolismo , Neutrófilos/metabolismo , Oxidantes/farmacologia , Fosfatos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Zimosan/farmacologia
8.
Int J Mol Sci ; 23(18)2022 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-36142809

RESUMO

Non-alcoholic fatty liver disease (NAFLD) affects up to 20% of the world's population. Overactivation of the angiotensin receptor type 1 (AT1) contributes to metabolic dysfunction and increased oxidant production, which are associated with NAFLD and impaired hepatic lipid metabolism. Nuclear factor erythroid-2-related factor 2 (Nrf2) regulates the expression of antioxidant phase II genes by binding to the antioxidant response element (ARE); however, the mechanisms by which AT1 contributes to this pathway during the progression of NAFLD remain unresolved. To investigate hepatic Nrf2 response to a hyperglycemic challenge, we studied three groups of rats (male, 10-weeks-old): (1) untreated, lean Long Evans Tokushima Otsuka (LETO), (2) untreated, obese Otsuka Long Evans Tokushima Fatty (OLETF), and (3) OLETF + angiotensin receptor blocker (OLETF + ARB; 10 mg olmesartan/kg/d × 6 weeks). Livers were collected after overnight fasting (T0; baseline), and 1 h and 2 h post-oral glucose load. At baseline, chronic AT1 blockade increased nuclear Nrf2 content, reduced expression of glutamate-cysteine ligase catalytic (GCLC) subunit, glutathione peroxidase 1 (GPx1), and superoxide dismutase 2 (SOD2), mitochondrial catalase activity, and hepatic 4-hydroxy-2-nonenal (4-HNE) content. The expression of hepatic interleukin-1 beta (IL-1ß) and collagen type IV, which are associated with liver fibrosis, were decreased with AT1 blockade. Glucose increased Nrf2 translocation in OLETF but was reduced in ARB, suggesting that glucose induces the need for antioxidant defense that is ameliorated with ARB. These results suggest that overactivation of AT1 promotes oxidant damage by suppressing Nrf2 and contributing to hepatic fibrosis associated with NAFLD development.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Antioxidantes/farmacologia , Catalase , Colágeno Tipo IV , Glucose/metabolismo , Glutamato-Cisteína Ligase , Insulina , Resistência à Insulina/fisiologia , Interleucina-1beta , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Obesidade/metabolismo , Oxidantes/farmacologia , Ratos , Receptores de Angiotensina
9.
Rev Assoc Med Bras (1992) ; 68(8): 1017-1022, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36134830

RESUMO

OBJECTIVE: We aimed to determine whether vitamin C has a protective effect on cisplatin-induced neuropathy in rats. METHODS: In total, 24 rats were included in the study of which 8 rats (no drug administered) were categorized as the control group. The remaining 16 rats were given a total dose of 20 mg/kg cisplatin to induce neuropathy. These drug-administered rats (16 rats) were randomly divided into two groups, namely, group-1 (n=8): cisplatin+saline and group-2 (n=8): cisplatin+vitamin C (500 mg/kg/day). All rats were tested for motor function and electromyographic activity 3 days after cisplatin. Motor performance was evaluated by an inclined-plane test. Compound muscle action potential was evaluated. Plasma malondialdehyde, glutathione, tumor necrosis factor-α, interleukin 6, and sciatic nerve HSP 70 levels were measured. Axon diameter and nerve growth factor expression levels were analyzed. RESULTS: Plasma malondialdehyde, tumor necrosis factor-α, and interleukin 6 levels were higher in the cisplatin+saline group than control group (p<0.001). But vitamin C significantly reduced malondialdehyde and inflammatory cytokine levels when compared with the cisplatin+saline group (p<0.001). Glutathione levels were lower in both cisplatin+saline and cisplatin+vitamin C groups than control group, but vitamin C significantly ameliorated the glutathione levels (p<0.05). Sciatic heat shock protein-70 levels were significantly higher in the cisplatin+vitamin C group than cisplatin+saline group. Compound muscle action potential amplitude and inclined plane test scores were significantly improved in the vitamin C group (p<0.05). Axon diameter and nerve growth factor expression ameliorated with vitamin C (p<0.05). CONCLUSIONS: We demonstrated the ameliorated effects of vitamin C on cisplatin-induced neuropathy through increased heat shock protein-70, nerve growth factor levels, and reduced inflammatory and oxidant effects. The results are promising to improve the neurotoxic effects of cisplatin in cancer patients.


Assuntos
Antineoplásicos , Doenças do Sistema Nervoso Periférico , Animais , Antineoplásicos/efeitos adversos , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Ácido Ascórbico/farmacologia , Ácido Ascórbico/uso terapêutico , Cisplatino/efeitos adversos , Citocinas/metabolismo , Glutationa , Proteínas de Choque Térmico HSP70 , Interleucina-6 , Malondialdeído , Fatores de Crescimento Neural/metabolismo , Fatores de Crescimento Neural/farmacologia , Oxidantes/farmacologia , Estresse Oxidativo , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/prevenção & controle , Ratos , Fator de Necrose Tumoral alfa , Vitaminas
10.
Sci Rep ; 12(1): 15235, 2022 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-36075939

RESUMO

Resveratrol (RSV), a non-flavonoid stilbene polyphenol, possesses anti-carcinogenic activities against all the major stages of cancer. Zein nanoparticles (ZN NPs) have been utilized successfully in delivery of variant therapeuticals by virtue of their histocompatible nature. The goal of this work was to comparatively explore the antiproliferative, pro-apoptotic and oxidative stress potentials of RSV-ZN NPs versus RSV against human colorectal carcinoma HCT-116 cells. ZN-RSV NPs were developed and assayed for particle size analysis and RSV diffusion. The selected formula obtained 137.6 ± 8.3 nm as mean particle size, 29.4 ± 1.8 mV zeta potential, 92.3 ± 3.6% encapsulation efficiency. IC50 of the selected formula was significantly lower against HCT-116 cells versus Caco-2 cells. Also, significantly enhanced cellular uptake was generated from RSV-ZN NPs versus free RSV. Enhanced apoptosis was concluded due to increased percentage cells in G2-M and pre-G1 phases. The pro-apoptotic potential was explained by caspase-3 and cleaved caspase-3 increased mRNA expression in addition to NF-κB and miRNA125b decreased expression. Biochemically, ZN-RSV NPs induced oxidative stress as demonstrated by enhanced reactive oxygen species (ROS) generation and endothelial nitric oxide synthase (eNOS) isoenzyme increased levels. Conclusively, ZN-RSV NPs obtained cell cycle inhibition supported with augmented cytotoxicity, uptake and oxidative stress markers levels in HCT-116 tumor cells in comparison with free RSV. These results indicated intensified chemopreventive profile of RSV due to effective delivery utilizing ZN nano-dispersion against colorectal carcinoma HCT-116 cells.


Assuntos
Neoplasias Colorretais , Nanopartículas , Zeína , Apoptose , Células CACO-2 , Caspase 3/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Células HCT116 , Humanos , Oxidantes/farmacologia , Resveratrol/farmacologia , Zeína/farmacologia
11.
mBio ; 13(5): e0192622, 2022 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-36073817

RESUMO

The ability to overcome stressful environments is critical for pathogen survival in the host. One challenge for bacteria is the exposure to reactive chlorine species (RCS), which are generated by innate immune cells as a critical part of the oxidative burst. Hypochlorous acid (HOCl) is the most potent antimicrobial RCS and is associated with extensive macromolecular damage in the phagocytized pathogen. However, bacteria have evolved defense strategies to alleviate the effects of HOCl-mediated damage. Among these are RCS-sensing transcriptional regulators that control the expression of HOCl-protective genes under non-stress and HOCl stress. Uropathogenic Escherichia coli (UPEC), the major causative agent of urinary tract infections (UTIs), is particularly exposed to infiltrating neutrophils during pathogenesis; however, their responses to and defenses from HOCl are still completely unexplored. Here, we present evidence that UPEC strains tolerate higher levels of HOCl and are better protected from neutrophil-mediated killing compared with other E. coli. Transcriptomic analysis of HOCl-stressed UPEC revealed the upregulation of an operon consisting of three genes, one of which encodes the transcriptional regulator RcrR. We identified RcrR as a HOCl-responsive transcriptional repressor, which, under non-stress conditions, is bound to the operator and represses the expression of its target genes. During HOCl exposure, however, the repressor forms reversible intermolecular disulfide bonds and dissociates from the DNA resulting in the derepression of the operon. Deletion of one of the target genes renders UPEC significantly more susceptible to HOCl and phagocytosis indicating that the HOCl-mediated induction of the regulon plays a major role for UPEC's HOCl resistance. IMPORTANCE How do pathogens deal with antimicrobial oxidants produced by the innate immune system during infection? Uropathogenic Escherichia coli (UPEC), the most common etiological agent of urinary tract infections (UTIs), is particularly exposed to infiltrating neutrophils and, therefore, must counter elevated levels of the antimicrobial oxidant HOCl to establish infection. Our study provides fundamentally new insights into a defense mechanism that enables UPEC to fend off the toxic effects of HOCl stress. Intriguingly, the defense system is predominantly found in UPEC and absent in noninvasive enteropathogenic E. coli. Our data suggest expression of the target gene rcrB is exclusively responsible for UPEC's increased HOCl tolerance in culture and contributes to UPEC's survival during phagocytosis. Thus, this novel HOCl stress defense system could potentially serve as an attractive drug target to increase the body's own capacity to fight UTIs.


Assuntos
Infecções por Escherichia coli , Proteínas de Escherichia coli , Infecções Urinárias , Escherichia coli Uropatogênica , Humanos , Escherichia coli Uropatogênica/metabolismo , Cloro/farmacologia , Cloro/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Ácido Hipocloroso/farmacologia , Escherichia , Infecções Urinárias/microbiologia , Infecções por Escherichia coli/microbiologia , Oxirredução , Antibacterianos/farmacologia , Oxidantes/farmacologia , Dissulfetos/metabolismo
12.
Plant Physiol Biochem ; 189: 104-114, 2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-36081232

RESUMO

Cadmium (Cd) and lead (Pb) pollution is a major environmental issue affecting plant production. Spermidine (Spd) is involved in plant response to abiotic stress. However, the role and associated mechanism of Spd under Cd + Pb combined stress are poorly understood. The potential protective role of Spd at different concentration on rice (Oryza sativa L.) seedlings exposed to Cd + Pb treatment was investigated by a hydroponic experiment in this study. The results showed that exogenous Spd enhanced the tolerance of rice seedlings to Cd + Pb stress, resulted in an increase in plant height, root length, fresh weight and dry weight of roots and shoots. Further, application of Spd decreased the contents of hydrogen peroxide, superoxide anion, malondialdehyde, and the accumulation of Cd and Pb, and increased the contents of mineral nutrient, carotenoids, chlorophyll, proline, soluble sugar, soluble protein, total phenol, flavonoid, anthocyanin, and antioxidant enzymes activities in roots and shoots of rice seedlings under Cd + Pb stress. Particularly, 0.5 mmol L-1 Spd was the most effective to alleviate the adverse impacts on growth and physiological metabolism of rice seedlings under Cd + Pb stress. Principal component analysis and heat map clustering established correlations between physio-biochemical parameters and further revealed Spd alleviated Cd + Pb damage in rice seedling was associated with inhibition of accumulation and translocation of Cd and Pb, increasing the contents of photosynthetic pigments and mineral nutrient and stimulation of antioxidative response and osmotic adjustment. Overall, our findings provide an important prospect for use of Spd in modulating Cd + Pb tolerance in rice plants. Spd could help to alleviate Cd + Pb damage through inhibition of accumulation and translocation of Cd and Pb and stimulation of oxidant-defense system and osmotic adjustment.


Assuntos
Oryza , Antocianinas/metabolismo , Antioxidantes/metabolismo , Cádmio/metabolismo , Carotenoides/metabolismo , Clorofila/metabolismo , Peróxido de Hidrogênio/metabolismo , Chumbo/metabolismo , Malondialdeído/metabolismo , Oryza/metabolismo , Oxidantes/metabolismo , Oxidantes/farmacologia , Fenóis/metabolismo , Raízes de Plantas/metabolismo , Prolina/metabolismo , Plântula/metabolismo , Espermidina/metabolismo , Espermidina/farmacologia , Açúcares/metabolismo , Superóxidos/metabolismo
13.
Pharmacol Res ; 184: 106400, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35988868

RESUMO

BACKGROUND AND OBJECTIVE: Bone loss occurs in several inflammatory diseases because of chronic persistent inflammation that activates osteoclasts (OCs) to increase bone resorption. Currently available antiresorptive drugs have severe side effects or contraindications. Herein, we explored the effects and mechanism of Alpinetin (Alp) on receptor activator of nuclear factor κB ligand (RANKL)-mediated OCs differentiation, function, and in inflammatory osteolysis of mice. METHOD: Primary mouse bone marrow-derived macrophages (BMMs) induced by RANKL and macrophage colony-stimulating factor (M-CSF) were utilized to test the impact of Alp on OCs differentiation, function, and intracellular reactive oxygen species (ROS) production, respectively. Expression of oxidant stress relevant factors and OCs specific genes were assessed via real-time quantitative PCR. Further, oxidative stress-related factors, NF-κB, MAPK, PI3K/AKT/GSK3-ß, and NFATc1 pathways were examined via Western blot. Finally, LPS-induced mouse calvarial osteolysis was used to investigate the effect of Alp on inflammatory osteolysis in vivo. RESULT: Alp suppressed OCs differentiation and resorption function, and down-regulated the ROS production. Alp inhibited IL-1ß, TNF-α and osteoclast-specific gene transcription. It also blocked the gene and protein expression of Nox1 and Keap1, but enhanced Nrf2, CAT, and HO-1 protein levels. Additionally, Alp suppressed the phosphorylation of PI3K and P38, and restrained the expression of osteoclast-specific gene Nfatc1 and its auto-amplification, hence minimizing LPS-induced osteolysis in mice. CONCLUSION: Alp is a novel candidate or therapeutics for the osteoclast-associated inflammatory osteolytic ailment.


Assuntos
Conservadores da Densidade Óssea , Osteólise , Animais , Conservadores da Densidade Óssea/farmacologia , Diferenciação Celular , Flavanonas , Quinase 3 da Glicogênio Sintase/metabolismo , Inflamação/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Lipopolissacarídeos/farmacologia , Fator Estimulador de Colônias de Macrófagos/metabolismo , Fator Estimulador de Colônias de Macrófagos/farmacologia , Fator Estimulador de Colônias de Macrófagos/uso terapêutico , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Osteoclastos , Osteólise/induzido quimicamente , Osteólise/tratamento farmacológico , Oxidantes/metabolismo , Oxidantes/farmacologia , Oxidantes/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ligante RANK/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
14.
Sci Rep ; 12(1): 13504, 2022 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-35931740

RESUMO

The increasing widespread use of lithium, which is preferred as an energy source in batteries produced for electric vehicles and in many electronic vehicles such as computers and mobile phones, has made it an important environmental pollutant. In this study, the toxicity profile of lithium carbonate (Li2CO3) was investigated with the Allium test, which is a bio-indicator test. Dose-related toxic effects were investigated using Li2CO3 at doses of 25 mg/L, 50 mg/L, and 100 mg/L. The toxicity profile was determined by examining physiological, cytotoxic, genotoxic, biochemical and anatomical effects. Physiological effects of Li2CO3 were determined by root length, injury rate, germination percentage and weight gain while cytotoxic effects were determined by mitotic index (MI) ratio and genotoxic effects were determined by micronucleus (MN) and chromosomal aberrations (CAs). The effect of Li2CO3 on antioxidant and oxidant dynamics was determined by examining glutathione (GSH), malondialdehyde (MDA), catalase (CAT) and superoxide dismutase (SOD) levels, and anatomical changes were investigated in the sections of root meristematic tissues. As a result, Li2CO3 exhibited a dose-dependent regression in germination-related parameters. This regression is directly related to the MI and 100 mg/L Li2CO3 reduced MI by 38% compared to the control group. MN and CAs were observed at high rates in the groups treated with Li2CO3. Fragments were found with the highest rate among CAs. Other damages were bridge, unequal distribution of chromatin, sticky chromosome, vagrant chromosome, irregular mitosis, reverse polarization and multipolar anaphase. The genotoxic effects were associated with Li2CO3-DNA interactions determined by molecular docking. The toxic effects of Li2CO3 are directly related to the deterioration of the antioxidant/oxidant balance in the cells. While MDA, an indicator of lipid peroxidation, increased by 59.1% in the group administered 100 mg/L Li2CO3, GSH, which has an important role in cell defense, decreased by 60.8%. Significant changes were also detected in the activities of SOD and CAT, two important enzymes in antioxidant defense, compared to the control. These toxic effects, which developed in the cells belonging to the lithium-treated groups, were also reflected in the tissue anatomy, and anatomical changes such as epidermis cell damage, cortex cell damage, flattened cell nucleus, thickening of the cortex cell wall and unclear vascular tissue were observed in the anatomical sections. The frequency of these changes also increased depending on the Li2CO3 dose. As a result, Li2CO3, which is one of the lithium compounds, and has become an important contaminant in the environment with increasing technological developments, caused a combined and versatile toxicity in Allium cepa L. meristematic cells, especially by causing deterioration in antioxidant/oxidant dynamics.


Assuntos
Antioxidantes , Carbonato de Lítio , Antioxidantes/farmacologia , Dano ao DNA , Glutationa/farmacologia , Carbonato de Lítio/toxicidade , Simulação de Acoplamento Molecular , Cebolas , Oxidantes/farmacologia , Raízes de Plantas , Superóxido Dismutase/farmacologia
15.
Neurotox Res ; 40(5): 1369-1379, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36040578

RESUMO

Silver nanoparticles (AgNPs) are widely used in a variety of consumer products because of their antibacterial and antifungal characteristics, but little is known about their toxicity to the brain. In this study, we investigated AgNP-induced neurotoxicity using the human neuroblastoma cancer (SH-SY5Y) cell line. After a 24 h treatment of AgNPs with two primary sizes (5 and 50 nm labeled as Ag-5 and Ag-50, respectively), a series of toxicological endpoints including cell viability, expression of proteins and genes in amyloid precursor protein (APP) amyloid hydrolysis process and ferritinophagy signaling pathways, oxidative stress, intracellular iron levels, and molecular regulators of iron metabolism were evaluated. Our results showed that both Ag-5 and Ag-50 induced notable neurotoxic effects on SH-SY5Y cells indicated by cell proliferation inhibition, increased BACE1 protein expression, and decreased APP and ADAM10 gene expression. Activation of nuclear receptor coactivator 4-mediated ferritinophagy and blockade of autophagic flux were induced by AgNPs, accompanied by intracellular iron accumulation and overexpression of divalent metal-ion transporter-1 and ferroportin1 in SH-SY5Y cells. In addition, AgNPs significantly decreased glutathione peroxidase 4 protein expression but increased malondialdehyde concentration, suggesting that AgNP-induced iron accumulation may trigger oxidative stress by disruption of the intracellular oxidant and antioxidant systems. In addition, compared with Ag-50, Ag-5 with higher cellular uptake efficiency caused more detrimental effects on SH-SY5Y cells. In conclusion, our findings demonstrated a size-dependent neurotoxicity in SH-SY5Y cells by AgNPs via ferritinophagy-mediated oxidative stress.


Assuntos
Nanopartículas Metálicas , Neuroblastoma , Síndromes Neurotóxicas , Secretases da Proteína Precursora do Amiloide , Precursor de Proteína beta-Amiloide/metabolismo , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antioxidantes/farmacologia , Ácido Aspártico Endopeptidases , Linhagem Celular Tumoral , Sobrevivência Celular , Humanos , Ferro/metabolismo , Ferro/toxicidade , Malondialdeído/metabolismo , Nanopartículas Metálicas/toxicidade , Coativadores de Receptor Nuclear/metabolismo , Oxidantes/farmacologia , Estresse Oxidativo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Prata/toxicidade
16.
Invest Ophthalmol Vis Sci ; 63(9): 30, 2022 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-36036912

RESUMO

Purpose: Tight junctions (TJs) form the structural basis of retinal pigment epithelium (RPE) barrier functions. Although oxidative stress contributes to age-related macular degeneration, it is unclear how RPE TJ integrity is controlled by redox balance. In this study, we investigated the protective roles of nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor, and heme oxygenase-1 (HO1), a heme-degrading enzyme encoded by the NRF2 target gene HMOX1. Methods: ARPE19 cell cultures and mice, including wild-type, Nrf2-/-, and RPE-specific NRF2-deficient mice, were treated with chemicals that impose oxidative stress or impact heme metabolism. In addition, NRF2 and HO1 expression in ARPE19 cells was knocked down by siRNA. TJ integrity was examined by anti-zonula occludens-1 staining of cultured cells or flatmount RPE tissues from mice. RPE barrier functions were evaluated by transepithelium electrical resistance in ARPE19 cells and immunofluorescence staining for albumin or dextran in eye histological sections. Results: TJ structures and RPE barrier functions were compromised due to oxidant exposure and NRF2 deficiency but were rescued by HO1 inducer. Furthermore, treatment with HO1 inhibitor or heme precursor is destructive to TJ structures and RPE barrier properties. Interestingly, both NRF2 and HO1 were upregulated under oxidative stress, probably as an adaptive response to mitigate oxidant-inflicted damages. Conclusions: Our data indicate that the NRF2-HO1 axis protects TJ integrity and RPE barrier functions by driving heme degradation.


Assuntos
Fator 2 Relacionado a NF-E2 , Epitélio Pigmentado da Retina , Animais , Heme/metabolismo , Heme/farmacologia , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Oxidantes/farmacologia , Estresse Oxidativo/fisiologia , Epitélio Pigmentado da Retina/patologia
17.
Transplant Proc ; 54(7): 1859-1864, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35985878

RESUMO

BACKGROUND: Our objective was to determine the levels of heavy metals, oxidants, and antioxidants in liver tissue of patients with chronic liver disease (CLD) compared with healthy living liver donors (LLDs). METHODS: We obtained liver specimens from patients undergoing liver transplant for CLD. Samples were also obtained from LLDs. Biochemical analyses were performed on all samples, and the levels of liver tissue, heavy metal, and oxidant-antioxidants biomarker levels in patients with CLD were compared with those measured in LLDs. RESULTS: One hundred and eighteen individuals were included for analyses. Fifty-nine were patients with CLD, and 59 were LLDs. The median levels of liver tissue of superoxide dismutase (P = .009), glutathione peroxidase (P = .042), total oxidant status (P = .006), oxidative stress index (P < .001), and copper (P = .035) were prominently more elevated in CLD than LLDs. On the other hand, the median levels of liver tissue of cadmium (P < .001), selenium (P = .042), and zinc (P < .001) levels were more elevated in the LLDs than patients with CLD. The 2 groups were similar in terms of total antioxidant status, manganese, arsenic, and lead levels. CONCLUSIONS: Superoxide accumulation in the liver was higher in patients with CLD. Concerning heavy metals, only the median tissue copper was elevated in patients with CLD with higher Cu/Zn ratio. Cadmium, selenium, and zinc were significantly higher in the healthy LLDs.


Assuntos
Hepatopatias , Metais Pesados , Selênio , Humanos , Cobre/análise , Cobre/farmacologia , Cádmio/análise , Cádmio/farmacologia , Antioxidantes/farmacologia , Selênio/farmacologia , Chumbo/farmacologia , Metais Pesados/efeitos adversos , Zinco , Fígado , Hepatopatias/diagnóstico , Hepatopatias/cirurgia , Oxidantes/farmacologia
18.
Biomolecules ; 12(8)2022 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-36008981

RESUMO

Prolonged elevated oxidative stress (OS) possesses negative effect on cell structure and functioning, and is associated with the development of numerous disorders. Naturally occurred anti-oxidant compounds reduce the oxidative stress in living organisms. In this review, antioxidant properties of ß-carotene, tocopherols and ascorbic acid are presented based on in vitro, in vivo and populational studies. Firstly, environmental factors contributing to the OS occurrence and intracellular sources of Reactive Oxygen Species (ROS) generation, as well as ROS-mediated cellular structure degradation, are introduced. Secondly, enzymatic and non-enzymatic mechanism of anti-oxidant defence against OS development, is presented. Furthermore, ROS-preventing mechanisms and effectiveness of ß-carotene, tocopherols and ascorbic acid as anti-oxidants are summarized, based on studies where different ROS-generating (oxidizing) agents are used. Oxidative stress biomarkers, as indicators on OS level and prevention by anti-oxidant supplementation, are presented with a focus on the methods (spectrophotometric, fluorometric, chromatographic, immuno-enzymatic) of their detection. Finally, the application of Raman spectroscopy and imaging as a tool for monitoring the effect of anti-oxidant (ß-carotene, ascorbic acid) on cell structure and metabolism, is proposed. Literature data gathered suggest that ß-carotene, tocopherols and ascorbic acid possess potential to mitigate oxidative stress in various biological systems. Moreover, Raman spectroscopy and imaging can be a valuable technique to study the effect of oxidative stress and anti-oxidant molecules in cell studies.


Assuntos
Antioxidantes , Ácido Ascórbico , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Humanos , Oxidantes/farmacologia , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Projetos de Pesquisa , Tocoferóis/farmacologia , beta Caroteno/metabolismo , beta Caroteno/farmacologia
19.
J Biochem Mol Toxicol ; 36(10): e23169, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35833322

RESUMO

Pentylenetetrazole (PTZ) is preferred for experimental epilepsy induction. PTZ damages brain and other organs by elevating oxidative substances. Vitamin U (Vit U) is sulfur derivative substance that proved to be an excellent antioxidant. The current study was intended to determine the protective role of Vit U on PTZ-induced brain damage. Male Sprague-Dawley rats were separated into four groups. The Control group (Group I), was given saline for 7 days intraperitoneally (i.p); Vit U (Group II) was given as 50 mg/kg/day for 7 days by gavage; PTZ was injected into animals (Group III) at a single dose of 60 mg/kg, by i.p; PTZ + Vit U group (Group IV) was administered PTZ and Vit U in same dose and time as aforementioned. After the experiment was terminated, brain tissues were taken for the preparation of homogenates. In the PTZ group, glutathione and lipid peroxidation levels, alkaline phosphatase, myeloperoxidase, xanthine oxidase, acetylcholine esterase, antioxidant enzyme activities, total oxidant status, oxidative stress index, reactive oxygen species, and nitric oxide levels were increased. However, total antioxidant capacity was decreased in the PTZ group. Vit U ameliorated these effects in the PTZ-induced brain damage. Consequently, we can suggest that Vit U protected brain tissue via its antioxidant feature against PTZ kindling epilepsy.


Assuntos
Lesões Encefálicas , Epilepsia , Vitamina U , Fosfatase Alcalina , Animais , Antioxidantes/metabolismo , Encéfalo/metabolismo , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Epilepsia/prevenção & controle , Glutationa/metabolismo , Masculino , Óxido Nítrico , Oxidantes/farmacologia , Estresse Oxidativo , Pentilenotetrazol/toxicidade , Peroxidase , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio , Enxofre/metabolismo , Vitamina U/farmacologia , Xantina Oxidase
20.
J Dent ; 125: 104241, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35878703

RESUMO

INTRODUCTION: Pulpitis results from the infiltration of mixed populations of bacteria which trigger inflammation in the dental pulp, causing significant disruption to these tissues. Clinically, pulpitis frequently leads to devitalization or extraction, as disinfection of the dental pulp while maintaining its vitality is extremely difficult. Here we describe the use of an electrocatalytic titanium dioxide (TiO2)-based apparatus adapted from water purification technology, which can efficiently deliver anti-microbial oxidants (e.g., hydroxyl radicals) when low voltages are applied. As these oxidants are also potentially harmful to pulp cells, oxidant exposure protocols that disrupt oral bacteria, yet are innocuous to dental pulp cells must be established. METHODS: Stem cells from Human Exfoliated Deciduous teeth (SHEDs) and mixed salivary bacteria were exposed to apparatus generated oxidants for time points of 15, 100 or 300 s. SHED apoptosis, necrosis, and vitality post exposure were analyzed by florescent marker staining and flow cytometry. Destruction of mixed salivary bacteria was analyzed by post exposure counts of adherent bacterial cells. RESULTS: When applied to SHEDs the apparatus generated oxidants do not significantly induce apoptosis or necrosis at any exposure time. SHED cell vitality is not decreased with apparatus exposure. Exposure to apparatus generated oxidants destroys mixed salivary bacteria, with significant destruction seen at 15 s and maximal destruction achieved at 100 s. CONCLUSIONS: This technology has the potential to be useful in the disinfection of deep lesions and pulp tissues, efficiently producing oxidants which eliminate bacteria but do not harm native pulp cells after relatively brief exposures. CLINICAL SIGNIFICANCE: Incomplete disinfection of inflamed dental pulp is a significant cause of pulp destruction, leading to devitalization or extraction. Novel technology which enhances the disinfection of the pulp may provide clinicians with treatments options that preserve pulp vitality and tooth structure.


Assuntos
Pulpite , Polpa Dentária/patologia , Humanos , Necrose/patologia , Oxidantes/farmacologia , Pulpite/patologia , Células-Tronco/patologia
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