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1.
Pestic Biochem Physiol ; 178: 104926, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34446202

RESUMO

Nucleoside diphosphate kinases (NDPKs) are widespread nucleotide-metabolizing enzymes that are involved in a variety of biological processes, including responses to oxidative stress. Although studies have been conducted on NDPKs in mammals and some plants, there is scant research on insect NDPKs, especially in honey bees. In the present study, we isolated AccNDPK from Apis cerana cerana. Sequence analysis showed that AccNDPK has high homology with many NDPKs and contains a highly conserved NDPK active site motif. Based on phylogenetic analysis, AccNDPK has a relatively recent evolutionary relationship with NDPKs in other hymenopteran insects. AccNDPK was found to be highly expressed in newly emerged honey bees and muscle tissues, and RT-qPCR analysis and bacteriostatic assays showed that the expression level of AccNDPK is affected by abnormal temperature, UV light, H2O2, heavy metals, and various pesticides. After AccNDPK knockdown, antioxidant-related genes, including AccCAT, AccCYP4G11, AccGSTS4, AccTpx1 and AccMsrA, were upregulated, whereas AccGSTD, AccGST1, AccHSP22.6 and AccTrx1 were downregulated. Furthermore, catalase (CAT), superoxide dismutase (SOD), and peroxidase (POD) activities were significantly increased, and the tolerance of bees to oxidative stress caused by cyhalothrin was reduced by silencing of AccNDPK. Given these findings, we speculate that AccNDPK plays an important role in the oxidative stress response of A. cerana cerana.


Assuntos
Peróxido de Hidrogênio , Núcleosídeo-Difosfato Quinase , Animais , Antioxidantes , Abelhas/genética , Núcleosídeo-Difosfato Quinase/genética , Estresse Oxidativo/genética , Filogenia
2.
FASEB J ; 35(9): e21827, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34383980

RESUMO

Neuron-derived orphan receptor 1, NR4A3 (Nor1)/NR4A3 is an orphan nuclear receptor involved in the transcriptional control of developmental and neurological functions. Oxidative stress-induced conditions are primarily associated with neurological defects in humans, yet the impact on Nor1-mediated transcription of neuronal genes remains with unknown mechanism. Here, we demonstrate that Nor1 is a non-conventional target of SUMO2/3 conjugation at Lys-137 contained in an atypic ψKxSP motif referred to as the pSuM. Nor1 pSuM SUMOylation differs from the canonical process with the obligate phosphorylation of Ser-139 by Ras signaling to create the required negatively charged interface for SUMOylation. Additional phosphorylation at sites flanking the pSuM is also mediated by the coordinated action of protein kinase casein kinase 2 to function as a small ubiquitin-like modifier enhancer, regulating Nor1-mediated transcription and proteasomal degradation. Nor1 responsive genes involved in cell proliferation and metabolism, such as activating transcription factor 3, cyclin D1, CASP8 and FADD-like apoptosis regulator, and enolase 3 were upregulated in response to pSuM disruption in mouse HT-22 hippocampal neuronal cells and human neuroblastoma SH-SY5Y cells. We also identified critical antioxidant genes, such as catalase, superoxide dismutase 1, and microsomal glutathione S-transferase 2, as responsive targets of Nor1 under pSuM regulation. Nor1 SUMOylation impaired gene transcription through less effective Nor1 chromatin binding and reduced enrichment of histone H3K27ac marks to gene promoters. These effects resulted in decreased neuronal cell growth, increased apoptosis, and reduced survival to oxidative stress damage, underlying the role of pSuM-modified Nor1 in redox homeostasis. Our findings uncover a hierarchical post-translational mechanism that dictates Nor1 non-canonical SUMOylation, disrupting Nor1 transcriptional competence, and neuroprotective redox sensitivity.


Assuntos
Sobrevivência Celular/genética , Proteínas de Ligação a DNA/genética , Receptores de Esteroides/genética , Receptores dos Hormônios Tireóideos/genética , Sumoilação/genética , Animais , Apoptose/genética , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/genética , Quinase do Ponto de Checagem 2/genética , Regulação da Expressão Gênica/genética , Células HEK293 , Hipocampo/metabolismo , Homeostase/genética , Humanos , Camundongos , Neuroblastoma/genética , Neurônios/metabolismo , Oxirredução , Estresse Oxidativo/genética , Fosforilação/genética , Regiões Promotoras Genéticas/genética , Processamento de Proteína Pós-Traducional/genética , Transcrição Genética/genética , Ativação Transcricional/genética , Regulação para Cima/genética
3.
Artigo em Inglês | MEDLINE | ID: mdl-34444074

RESUMO

Smoking and lead (Pb) exposure increased oxidative stress in human body, and people with some gene variants may be susceptible to Pb and smoking via oxidative stress. The aim of this study is to evaluate oxidative stress by measuring thiobarbituric acid reactive substances (TBARS) and the relationship of lipid peroxidation markers in Pb workers with different gene polymorphisms (rs4673 and rs1050450) in both smokers and nonsmokers. Blood samples were collected from 267 Pb workers who received their annual health examination in the Kaohsiung Medical University Hospital. Glutathione peroxidase 1 (GPx-1) rs1050450 and cytochrome B-245 Alpha Chain (CYBA) rs4673 single-nucleotide polymorphisms (SNP) were analyzed by specific primer-probes using Real-Time PCR methods. The interaction between blood Pb and smoking increased serum levels of TBARS and the ratio of oxidative low-density lipoprotein and low-density lipoprotein (oxLDL/LDL). Analysis of workers with rs1050450 SNPs showed higher blood Pb levels in the workers with CC genotype than those with CT genotype. Smokers had significantly higher blood Pb, alanine transaminase (ALT), TBARS, and OxLDL levels than nonsmokers. TBARS increased 0.009 nmol/mL when blood Pb increased one µg/dL in smokers compared to nonsmokers. The ratio of OxLDL/LDL increased 0.223 when blood Pb increased one µg/dL in smokers compared to nonsmokers. TBARS levels and the ratio of OxLDL/LDL were positively correlated and interacted between blood Pb and smoking after the adjustment of confounders, suggesting that smoking cessation is an important issue in the Pb-exposed working environment.


Assuntos
Chumbo , Estresse Oxidativo , Fumar/efeitos adversos , Humanos , Chumbo/efeitos adversos , Peroxidação de Lipídeos , Estresse Oxidativo/genética , Substâncias Reativas com Ácido Tiobarbitúrico
4.
Int J Mol Sci ; 22(16)2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34445793

RESUMO

Spaceflight causes cardiovascular changes due to microgravity-induced redistribution of body fluids and musculoskeletal unloading. Cardiac deconditioning and atrophy on Earth are associated with altered Trp53 and oxidative stress-related pathways, but the effects of spaceflight on cardiac changes at the molecular level are less understood. We tested the hypothesis that spaceflight alters the expression of key genes related to stress response pathways, which may contribute to cardiovascular deconditioning during extended spaceflight. Mice were exposed to spaceflight for 15 days or maintained on Earth (ground control). Ventricle tissue was harvested starting ~3 h post-landing. We measured expression of select genes implicated in oxidative stress pathways and Trp53 signaling by quantitative PCR. Cardiac expression levels of 37 of 168 genes tested were altered after spaceflight. Spaceflight downregulated transcription factor, Nfe2l2 (Nrf2), upregulated Nox1 and downregulated Ptgs2, suggesting a persistent increase in oxidative stress-related target genes. Spaceflight also substantially upregulated Cdkn1a (p21) and cell cycle/apoptosis-related gene Myc, and downregulated the inflammatory response gene Tnf. There were no changes in apoptosis-related genes such as Trp53. Spaceflight altered the expression of genes regulating redox balance, cell cycle and senescence in cardiac tissue of mice. Thus, spaceflight may contribute to cardiac dysfunction due to oxidative stress.


Assuntos
Ciclo Celular/genética , Regulação da Expressão Gênica/genética , Genes cdc/genética , Coração/fisiologia , Estresse Oxidativo/genética , Animais , Apoptose/genética , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Oxirredução , Transdução de Sinais/genética , Voo Espacial/métodos , Ausência de Peso
5.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199458

RESUMO

As we age, our bodies accrue damage in the form of DNA mutations. These mutations lead to the generation of sub-optimal proteins, resulting in inadequate cellular homeostasis and senescence. The build-up of senescent cells negatively affects the local cellular micro-environment and drives ageing associated disease, including neurodegeneration. Therefore, limiting the accumulation of DNA damage is essential for healthy neuronal populations. The naked mole rats (NMR) are from eastern Africa and can live for over three decades in chronically hypoxic environments. Despite their long lifespan, NMRs show little to no biological decline, neurodegeneration, or senescence. Here, we discuss molecular pathways and adaptations that NMRs employ to maintain genome integrity and combat the physiological and pathological decline in organismal function.


Assuntos
Adaptação Fisiológica/genética , Senescência Celular/genética , Dano ao DNA/genética , Estresse Oxidativo/genética , Envelhecimento/genética , Animais , DNA/genética , Homeostase , Ratos-Toupeira/genética , Estresse Oxidativo/fisiologia
6.
Arch Insect Biochem Physiol ; 108(1): e21830, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34288081

RESUMO

Zinc finger proteins (ZFPs) are a class of transcription factors that contain zinc finger domains and play important roles in growth, aging, and responses to abiotic and biotic stresses. These proteins activate or inhibit gene transcription by binding to single-stranded DNA or RNA and through RNA/DNA bidirectional binding and protein-protein interactions. However, few studies have focused on the oxidation resistance functions of ZFPs in insects, particularly Apis cerana. In the current study, we identified a ZFP41 gene from A. cerana, AcZFP41, and verified its function in oxidative stress responses. Real-time quantitative polymerase chain reaction showed that the transcription level of AcZFP41 was upregulated to different degrees during exposure to oxidative stress, including that induced by extreme temperature, UV radiation, or pesticides. In addition, the silencing of AcZFP41 led to changes in the expression patterns of some known antioxidant genes. Moreover, the activities of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD), peroxidase (POD), and glutathione S-transferase (GST) in AcZFP41-silenced honeybees were higher than those in a control group. In summary, the data indicate that AcZFP41 is involved in the oxidative stress response. The results provide a theoretical basis for further studies of zinc finger proteins and improve our understanding of the antioxidant mechanisms of honeybees.


Assuntos
Abelhas , Estresse Oxidativo/genética , Estresse Fisiológico/genética , Dedos de Zinco/genética , Animais , Antioxidantes/metabolismo , Abelhas/genética , Abelhas/metabolismo , Abelhas/fisiologia , Glutationa Transferase/metabolismo , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Peroxidase/metabolismo , Interferência de RNA , Superóxido Dismutase/metabolismo , Dedos de Zinco/fisiologia
7.
Free Radic Biol Med ; 173: 117-124, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34303830

RESUMO

BACKGROUND: Congenital hereditary endothelial dystrophy (CHED) is a rare genetic disease of the corneal endothelium with a very early onset of bilateral corneal edema due to degeneration and dysfunction of the corneal endothelium. Currently SLC4A11 is the only established causative gene for CHED, but not all these reported CHED patients could be explained by SLC4A11 deficiency, indicating that the genetic predisposition of CHED still requires further exploration. METHODS: Trio-based whole-exome sequencing was performed on a CHED patient and his unaffected parents. The GATK2 and an in-house bioinformatics pipeline were applied for variant analyses, following the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines. Potential pathogenic variants were further validated by Sanger sequencing. The expression profiles of FAM149A in cell line, murine tissues or human corneal endothelia were determined by RT-qPCR. Small interfering RNA was used to knock down the expression of FAM149A in vitro. Cell viability was detected by a CCK-8 assay. ROS and 8-OHdG were examined by fluorometric analysis. The nuclear translocation of NRF2 was determined by western blotting. RESULTS: We identified a homozygous mutation (NM_015398.3: c.991A > G; p.R331G) in the FAM149A gene that related to the phenotype of CHED. FAM149A was found to be highly expressed in corneal endothelium, and up-regulated upon oxidative stress. Further functional investigations demonstrated that deficiency in FAM149A impaired Nrf2-antioxidant signaling, rendering cells more vulnerable to oxidative stress. Consistently, the expression of FAM149A was significantly reduced in patients with corneal endothelium dysfunction. CONCLUSION: This study demonstrated, for the first time, FAM149A as a plausible causative gene for CHED etiology, offering new insight for future investigation targeting CHED.


Assuntos
Distrofias Hereditárias da Córnea , Proteínas , Simportadores , Animais , Proteínas de Transporte de Ânions/genética , Proteínas de Transporte de Ânions/metabolismo , Antioxidantes , Antiporters/genética , Antiporters/metabolismo , Distrofias Hereditárias da Córnea/genética , Humanos , Camundongos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/genética , Proteínas/genética , Sequenciamento Completo do Exoma
8.
Mol Med Rep ; 24(4)2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34328194

RESUMO

Previous studies have suggested that oxidative stress and autophagy results in acute kidney injury (AKI) during sepsis and microRNA (miR)­214 serves a vital role in the protection of kidneys subjected to oxidative stress. The present study aimed to test whether the renoprotection of miR­214 is related to autophagy in sepsis. The role of autophagy was investigated in a mouse model of cecal ligation and puncture (CLP). Reverse transcription­quantitative polymerase chain reaction (RT­qPCR) was used to analyze the expression of miR­214. The structure and function of kidneys harvested from the mice were evaluated. Kidney autophagy levels were detected with immunohistochemical, immunofluorescent and western blotting. It was found that miR­214 could alleviate AKI in septic mice by inhibiting the level of kidney autophagy. Furthermore, miR­214 inhibited autophagy by silencing PTEN expression in the kidney tissues of septic mice. These findings indicated that miR­214 ameliorated CLP­induced AKI by reducing oxidative stress and inhibiting autophagy through the regulation of the PTEN/AKT/mTOR pathway.


Assuntos
Injúria Renal Aguda/genética , Autofagia/genética , MicroRNAs/genética , MicroRNAs/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Animais , Ceco/lesões , Ceco/microbiologia , Modelos Animais de Doenças , Rim/metabolismo , Rim/patologia , Rim/ultraestrutura , Ligadura , Masculino , Camundongos , Estresse Oxidativo/genética , PTEN Fosfo-Hidrolase/genética , Punções , Sepse/complicações , Transdução de Sinais/genética
9.
Mol Med Rep ; 24(4)2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34328196

RESUMO

Inflammation and oxidative stress have indispensable roles in the development of acute lung injury (ALI). MicroRNA (miRNA/miR)­351­5p was initially identified as a myogenesis­associated miRNA; however, its role in lipopolysaccharide (LPS)­induced ALI remains unclear. The aim of the present study was to investigate the role and potential mechanisms of miR­351­5p in ALI. ALI was induced through a single intratracheal injection of LPS for 12 h, and miR­351­5p agomir, antagomir or their corresponding negative controls were injected into the tail vein before LPS stimulation. Compound C, 2',5'­dideoxyadenosine and H89 were used to inhibit AMP­activated protein kinase (AMPK), adenylate cyclase and protein kinase A (PKA), respectively. miR­351­5p levels in the lungs were significantly increased in response to LPS injection. miR­351­5p antagomir alleviated, while miR­351­5p agomir aggravated LPS­induced oxidative stress and inflammation in the lungs. The present results also demonstrated that miR­351­5p antagomir attenuated LPS­induced ALI via activating AMPK, and that the cAMP/PKA axis was required for the activation of AMPK by the miR­351­5p antagomir. In conclusion, the present study indicated that miR­351­5p aggravated LPS­induced ALI via inhibiting AMPK, suggesting that targeting miR­351­5p may help to develop efficient therapeutic approaches for treating ALI.


Assuntos
Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Animais , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Modelos Animais de Doenças , Inflamação/genética , Lipopolissacarídeos/toxicidade , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/agonistas , MicroRNAs/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estresse Oxidativo/genética
10.
Free Radic Biol Med ; 174: 89-99, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34324980

RESUMO

Although DNA repair is known to impact susceptibility to cancer and other diseases, relatively few population studies have been performed to evaluate DNA repair kinetics in people due to the difficulty of assessing DNA repair in a high-throughput manner. Here we use the CometChip, a high-throughput comet assay, to explore inter-individual variation in repair of oxidative damage to DNA, a known risk factor for aging, cancer and other diseases. DNA repair capacity after H2O2-induced DNA oxidation damage was quantified in peripheral blood mononuclear cells (PBMCs). For 10 individuals, blood was drawn at several times over the course of 4-6 weeks. In addition, blood was drawn once from each of 56 individuals. DNA damage levels were quantified prior to exposure to H2O2 and at 0, 15, 30, 60, and 120-min post exposure. We found that there is significant variability in DNA repair efficiency among individuals. When subdivided into quartiles by DNA repair efficiency, we found that the average t1/2 is 81 min for the slowest group and 24 min for the fastest group. This work shows that the CometChip can be used to uncover significant differences in repair kinetics among people, pointing to its utility in future epidemiological and clinical studies.


Assuntos
Peróxido de Hidrogênio , Leucócitos Mononucleares , Ensaio Cometa , Dano ao DNA , Reparo do DNA , Humanos , Individualidade , Cinética , Linfócitos , Estresse Oxidativo/genética
11.
Free Radic Biol Med ; 174: 28-39, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34324982

RESUMO

Glutathione (GSH) is a critical cellular antioxidant that protects against byproducts of aerobic metabolism and other reactive electrophiles to prevent oxidative stress and cell death. Proper maintenance of its reduced form, GSH, in excess of its oxidized form, GSSG, prevents oxidative stress in the kidney and protects against the development of chronic kidney disease. Evidence has indicated that renal concentrations of GSH and GSSG, as well as their ratio GSH/GSSG, are moderately heritable, and past research has identified polymorphisms and candidate genes associated with these phenotypes in mice. Yet those discoveries were made with in silico mapping methods that are prone to false positives and power limitations, so the true loci and candidate genes that control renal glutathione remain unknown. The present study utilized high-resolution gene mapping with the Diversity Outbred mouse stock to identify causal loci underlying variation in renal GSH levels and redox status. Mapping output identified a suggestive locus associated with renal GSH on murine chromosome X at 51.602 Mbp, and bioinformatic analyses identified apoptosis-inducing factor mitochondria-associated 1 (Aifm1) as the most plausible candidate. Then, mapping outputs were compiled and compared against the genetic architecture of the hepatic GSH system, and we discovered a locus on murine chromosome 14 that overlaps between hepatic GSH concentrations and renal GSH redox potential. Overall, the results support our previously proposed model that the GSH redox system is regulated by both global and tissue-specific loci, vastly improving our understanding of GSH and its regulation and proposing new candidate genes for future mechanistic studies.


Assuntos
Glutationa , Estresse Oxidativo , Animais , Mapeamento Cromossômico , Glutationa/metabolismo , Dissulfeto de Glutationa/metabolismo , Rim/metabolismo , Camundongos , Oxirredução , Estresse Oxidativo/genética , Cromossomo X/metabolismo
12.
Anticancer Res ; 41(7): 3261-3270, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230120

RESUMO

BACKGROUND/AIM: Chronic inflammation generates large quantities of reactive oxygen and nitrogen species that damage DNA. DNA repair is important for cellular viability and genome integrity. MATERIALS AND METHODS: Expression levels of the DNA repair proteins OGG1, XPA, MLH1, PARP1, and XRCC6, which function in base excision repair, nucleotide excision repair, mismatch repair, single-strand break repair and double-strand break repair, respectively, were assessed using immunohistochemistry in ulcerative colitis and sporadic colorectal cancer biopsies. Levels of oxidative/ nitrosative stress biomarkers were also assessed. RESULTS: Ulcerative colitis and colorectal cancer lesions expressed significantly higher levels of all DNA repair proteins and oxidative/ nitrosative stress biomarkers compared to normal colonic mucosa. Ulcerative colitis had the highest XPA and XRCC6 expression. CONCLUSION: Oxidative/nitrosative stress is prevalent in the colon of both diseases. Nucleotide excision repair and non-homologous end-joining double-strand break repair may be compromised in colorectal cancer, but not in ulcerative colitis.


Assuntos
Colite Ulcerativa/genética , Neoplasias Colorretais/genética , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , DNA/genética , Estresse Nitrosativo/genética , Estresse Oxidativo/genética , Biomarcadores Tumorais/genética , Colite Ulcerativa/patologia , Colo/patologia , Neoplasias Colorretais/patologia , Dano ao DNA/genética , Humanos , Mucosa Intestinal/patologia , Oxirredução
13.
Int J Mol Sci ; 22(14)2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34298930

RESUMO

(1) Background: Non-alcoholic fatty liver disease (NAFLD) is a growing global health problem. NAFLD progression involves a complex interplay of imbalanced inflammatory cell populations and inflammatory signals such as reactive oxygen species and cytokines. These signals can derive from the liver itself but also from adipose tissue or be mediated via changes in the gut microbiome. We analyzed the effects of a simultaneous migration blockade caused by L-selectin-deficiency and an enhancement of the anti-oxidative stress response triggered by hepatocytic Kelch-like ECH-associated protein 1 (Keap1) deletion on NAFLD progression. (2) Methods: L-selectin-deficient mice (Lsel-/-Keap1flx/flx) and littermates with selective hepatic Keap1 deletion (Lsel-/-Keap1Δhepa) were compared in a 24-week Western-style diet (WD) model. (3) Results: Lsel-/-Keap1Δhepa mice exhibited increased expression of erythroid 2-related factor 2 (Nrf2) target genes in the liver, decreased body weight, reduced epidydimal white adipose tissue with decreased immune cell frequencies, and improved glucose response when compared to their Lsel-/-Keap1flx/flx littermates. Although WD feeding caused drastic changes in fecal microbiota profiles with decreased microbial diversity, no genotype-dependent shifts were observed. (4) Conclusions: Upregulation of the anti-oxidative stress response improves metabolic changes in L-selectin-deficient mice but does not prevent NAFLD progression and shifts in the gut microbiota.


Assuntos
Fezes/microbiologia , Selectina L/genética , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Estresse Oxidativo/genética , Regulação para Cima/genética , Animais , Dieta Ocidental , Microbioma Gastrointestinal/genética , Hepatócitos/metabolismo , Hepatócitos/patologia , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/genética
14.
Int J Mol Sci ; 22(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34205045

RESUMO

SGLT-2i's exert direct anti-inflammatory and anti-oxidative effects on resting endothelial cells. However, endothelial cells are constantly exposed to mechanical forces such as cyclic stretch. Enhanced stretch increases the production of reactive oxygen species (ROS) and thereby impairs endothelial barrier function. We hypothesized that the SGLT-2i's empagliflozin (EMPA), dapagliflozin (DAPA) and canagliflozin (CANA) exert an anti-oxidative effect and alleviate cyclic stretch-induced endothelial permeability in human coronary artery endothelial cells (HCAECs). HCAECs were pre-incubated with one of the SGLT-2i's (1 µM EMPA, 1 µM DAPA and 3 µM CANA) for 2 h, followed by 10% stretch for 24 h. HCAECs exposed to 5% stretch were considered as control. Involvement of ROS was measured using N-acetyl-l-cysteine (NAC). The sodium-hydrogen exchanger 1 (NHE1) and NADPH oxidases (NOXs) were inhibited by cariporide, or GKT136901, respectively. Cell permeability and ROS were investigated by fluorescence intensity imaging. Cell permeability and ROS production were increased by 10% stretch; EMPA, DAPA and CANA decreased this effect significantly. Cariporide and GKT136901 inhibited stretch-induced ROS production but neither of them further reduced ROS production when combined with EMPA. SGLT-2i's improve the barrier dysfunction of HCAECs under enhanced stretch and this effect might be mediated through scavenging of ROS. Anti-oxidative effect of SGLT-2i's might be partially mediated by inhibition of NHE1 and NOXs.


Assuntos
Células Endoteliais/efeitos dos fármacos , Inflamação/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Proteínas de Transporte de Sódio-Glucose/antagonistas & inibidores , Trocador 1 de Sódio-Hidrogênio/antagonistas & inibidores , Compostos Benzidrílicos/farmacologia , Canagliflozina/farmacologia , Permeabilidade da Membrana Celular/efeitos dos fármacos , Células Endoteliais/metabolismo , Glucosídeos/farmacologia , Guanidinas/farmacologia , Humanos , Inflamação/genética , Inflamação/patologia , NADPH Oxidases/antagonistas & inibidores , NADPH Oxidases/genética , Estresse Oxidativo/genética , Pirazóis/farmacologia , Piridonas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Proteínas de Transporte de Sódio-Glucose/genética , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Trocador 1 de Sódio-Hidrogênio/genética , Estresse Mecânico , Sulfonas/farmacologia
15.
Int J Mol Sci ; 22(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34206048

RESUMO

Acrylamide is a well characterized neurotoxicant known to cause neuropathy and encephalopathy in humans and experimental animals. To investigate the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in acrylamide-induced neuropathy, male C57Bl/6JJcl adult mice were exposed to acrylamide at 0, 200 or 300 ppm in drinking water and co-administered with subcutaneous injections of sulforaphane, a known activator of the Nrf2 signaling pathway at 0 or 25 mg/kg body weight daily for 4 weeks. Assessments for neurotoxicity, hepatotoxicity, oxidative stress as well as messenger RNA-expression analysis for Nrf2-antioxidant and pro-inflammatory cytokine genes were conducted. Relative to mice exposed only to acrylamide, co-administration of sulforaphane protected against acrylamide-induced neurotoxic effects such as increase in landing foot spread or decrease in density of noradrenergic axons as well as hepatic necrosis and hemorrhage. Moreover, co-administration of sulforaphane enhanced acrylamide-induced mRNA upregulation of Nrf2 and its downstream antioxidant proteins and suppressed acrylamide-induced mRNA upregulation of tumor necrosis factor alpha (TNF-α) and inducible nitric oxide synthase (iNOS) in the cerebral cortex. The results demonstrate that activation of the Nrf2 signaling pathway by co-treatment of sulforaphane provides protection against acrylamide-induced neurotoxicity through suppression of oxidative stress and inflammation. Nrf2 remains an important target for the strategic prevention of acrylamide-induced neurotoxicity.


Assuntos
Inflamação/genética , Isotiocianatos/farmacologia , Fator 2 Relacionado a NF-E2/genética , Síndromes Neurotóxicas/genética , Sulfóxidos/farmacologia , Acrilamida/toxicidade , Animais , Modelos Animais de Doenças , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/patologia , Camundongos , Microglia/metabolismo , Microglia/patologia , NF-kappa B/genética , Síndromes Neurotóxicas/tratamento farmacológico , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/patologia , Óxido Nítrico Sintase Tipo II/genética , Estresse Oxidativo/genética , Transdução de Sinais/efeitos dos fármacos
16.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199527

RESUMO

Overactive bladder (OAB) syndrome, including frequency, urgency, nocturia and urgency incontinence, has a significantly negative impact on the quality-of-life scale (QoL) and can cause sufferer withdrawal from social activities. The occurrence of OAB can result from an imbalance between the production of pro-oxidants, such as free radicals and reactive species, and their elimination through protective mechanisms of antioxidant-induced oxidative stress. Several animal models, such as bladder ischemia/reperfusion (I/R), partial bladder outlet obstruction (PBOO) and ovarian hormone deficiency (OHD), have suggested that cyclic I/R during the micturition cycle induces oxidative stress, leading to bladder denervation, bladder afferent pathway sensitization and overexpression of bladder-damaging molecules, and finally resulting in bladder hyperactivity. Based on the results of previous animal experiments, the present review specifically focuses on four issues: (1) oxidative stress and antioxidant defense system; (2) oxidative stress in OAB and biomarkers of OAB; (3) OAB animal model; (4) potential nature/plant antioxidant treatment strategies for urinary dysfunction with OAB. Moreover, we organized the relationships between urinary dysfunction and oxidative stress biomarkers in urine, blood and bladder tissue. Reviewed information also revealed the summary of research findings for the effects of various antioxidants for treatment strategies for OAB.


Assuntos
Antioxidantes/uso terapêutico , Isquemia/tratamento farmacológico , Bexiga Urinária Hiperativa/tratamento farmacológico , Incontinência Urinária/tratamento farmacológico , Humanos , Isquemia/patologia , Estresse Oxidativo/genética , Estresse Oxidativo/fisiologia , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/patologia , Incontinência Urinária/patologia
17.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199590

RESUMO

In living cells Reactive Oxygen Species (ROS) participate in intra- and inter-cellular signaling and all cells contain specific systems that guard redox homeostasis. These systems contain both enzymes which may produce ROS such as NADPH-dependent and other oxidases or nitric oxide synthases, and ROS-neutralizing enzymes such as catalase, peroxiredoxins, thioredoxins, thioredoxin reductases, glutathione reductases, and many others. Most of the genes coding for these enzymes contain sequences targeted by micro RNAs (miRNAs), which are components of RNA-induced silencing complexes and play important roles in inhibiting translation of their targeted messenger RNAs (mRNAs). In this review we describe miRNAs that directly target and can influence enzymes responsible for scavenging of ROS and their possible role in cellular redox homeostasis. Regulation of antioxidant enzymes aims to adjust cells to survive in unstable oxidative environments; however, sometimes seemingly paradoxical phenomena appear where oxidative stress induces an increase in the levels of miRNAs which target genes which are supposed to neutralize ROS and therefore would be expected to decrease antioxidant levels. Here we show examples of such cellular behaviors and discuss the possible roles of miRNAs in redox regulatory circuits and further cell responses to stress.


Assuntos
Antioxidantes/metabolismo , Homeostase/genética , MicroRNAs/genética , Estresse Oxidativo/genética , Glutationa Redutase/genética , Glutationa Redutase/metabolismo , Humanos , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase/metabolismo , Oxirredução , Peroxirredoxinas/genética , Peroxirredoxinas/metabolismo , Tiorredoxinas/genética , Tiorredoxinas/metabolismo
18.
Neurosci Biobehav Rev ; 128: 534-548, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34216652

RESUMO

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by behavioral deficits including impairments in social communication, social interaction, and repetitive behaviors. Because the etiology of ASD is still largely unknown, there is no cure for ASD thus far. Although it has been established that genetic components play a vital role in ASD development, the influence of epigenetic regulation induced by environmental factors could also contribute to ASD susceptibility. Accumulated evidence has suggested that exposure to atmospheric particulate matter (PM) in polluted air could affect neurodevelopment, thus possibly leading to ASD. Particles with a size of 2.5 µm (PM2.5) or less have been shown to have negative effects on human health, and could be linked to ASD symptoms in children. This review summarizes evidence from clinical and animal studies to demonstrate the possible linkage between PM2.5 exposure and the incidence of ASD in children. An attempt was made to explore the possible mechanisms of this linkage, including changes of gene expression, oxidative stress and neuroinflammation induced by PM2.5 exposure.


Assuntos
Transtorno do Espectro Autista , Material Particulado , Animais , Transtorno do Espectro Autista/genética , Criança , Epigênese Genética , Expressão Gênica , Humanos , Estresse Oxidativo/genética , Material Particulado/toxicidade , Fatores de Risco
19.
Aging (Albany NY) ; 13(13): 17592-17606, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34237708

RESUMO

Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the two most common pathology subtypes of primary liver cancer (PLC). Identifying DNA methylation biomarkers for diagnosis of PLC and further distinguishing HCC from ICC plays a vital role in subsequent treatment options selection. To obtain potential diagnostic DNA methylation sites for PLC, differentially methylated CpG (DMC) sites were first screened by comparing the methylation data between normal liver samples and PLC samples (ICC samples and HCC samples). A random forest algorithm was then used to select specific DMC sites with top Gini value. To avoid overfitting, another cohort was taken as an external validation for evaluating the area under curves (AUCs) of different DMC sites combination. A similar model construction strategy was applied to distinguish HCC from ICC. In addition, we identified DNA Methylation-Driven Genes in HCC and ICC via MethylMix method and performed pathway analysis by utilizing MetaCore. Finally, we not only performed methylator phenotype based on independent prognostic sites but also analyzed the correlations between methylator phenotype and clinical factors in HCC and ICC, respectively. To diagnose PLC, we developed a model based on three PLC-specific methylation sites (cg24035245, cg21072795, and cg00261162), whose sensitivity and specificity achieved 98.8%,94.8% in training set and 97.3%,81% in validation set. Then, to further divide the PLC samples into HCC and ICC, we established another mode through three methylation sites (cg17769836, cg17591574, and cg07823562), HCC accuracy and ICC accuracy achieved 95.8%, 89.8% in the training set and 96.8%,85.4% in the validation set. In HCC, the enrichment pathways were mainly related to protein folding, oxidative stress, and glutathione metabolism. While in ICC, immune response, embryonic hepatocyte maturation were the top pathways. Both in HCC and ICC, methylator phenotype correlated well with overall survival time and clinical factors involved in tumor progression. In summary, our study provides the biomarkers based on methylation sites not only for the diagnosis of PLC but also for distinguishing HCC from ICC.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/genética , Metilação de DNA/genética , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Algoritmos , Estudos de Coortes , Diagnóstico Diferencial , Glutationa/metabolismo , Hepatócitos/patologia , Humanos , Estresse Oxidativo/genética , Valor Preditivo dos Testes , Prognóstico , Dobramento de Proteína , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
20.
Theranostics ; 11(14): 6766-6785, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093852

RESUMO

Endothelial cells (ECs) constitute the innermost layer in all blood vessels to maintain the structural integrity and microcirculation function for coronary microvasculature. Impaired endothelial function is demonstrated in various cardiovascular diseases including myocardial infarction (MI), which is featured by reduced myocardial blood flow as a result of epicardial coronary obstruction, thrombogenesis, and inflammation. In this context, understanding the cellular and molecular mechanisms governing the function of coronary ECs is essential for the early diagnosis and optimal treatment of MI. Although ECs contain relatively fewer mitochondria compared with cardiomyocytes, they function as key sensors of environmental and cellular stress, in the regulation of EC viability, structural integrity and function. Mitochondrial quality control (MQC) machineries respond to a broad array of stress stimuli to regulate fission, fusion, mitophagy and biogenesis in mitochondria. Impaired MQC is a cardinal feature of EC injury and dysfunction. Hence, medications modulating MQC mechanisms are considered as promising novel therapeutic options in MI. Here in this review, we provide updated insights into the key role of MQC mechanisms in coronary ECs and microvascular dysfunction in MI. We also discussed the option of MQC as a novel therapeutic target to delay, reverse or repair coronary microvascular damage in MI. Contemporary available MQC-targeted therapies with potential clinical benefits to alleviate coronary microvascular injury during MI are also summarized.


Assuntos
Células Endoteliais/metabolismo , Microvasos/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Dinâmica Mitocondrial/efeitos dos fármacos , Infarto do Miocárdio/metabolismo , Animais , Humanos , Inflamação/metabolismo , Microvasos/patologia , Mitocôndrias/genética , Dinâmica Mitocondrial/genética , Mitofagia/genética , Infarto do Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
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