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1.
Behav Brain Res ; 437: 114163, 2023 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-36265761

RESUMO

Sodium benzoate (SB) is a commonly-used food preservative, with a controversial report to its neurological benefit and toxicity. Zinc (Zn) is a trace element that plays a crucial role in memory, inflammation and oxidative stress. This study was to investigate the effect of SB on rat cognition and memory and the possible modulatory effect of Zn supplement. Twenty four male Wistar rats were divided into four groups of six animals each. Animals in groups 1-4 were treated with normal saline 1 ml/kg, SB 200 mg/kg, zinc sulphate 10 ml/kg and SB 200 mg/kg + zinc sulphate 10 ml/kg/day daily respectively for three weeks. After treatment, the animals were subjected to different behavioural tests, and then sacrificed. Their blood samples were collected for catalase(CAT), superoxide dismutase(SOD) and interleukin-1B(IL-1B) assay. Brain samples were also collected for nuclear factor-erythroid-related factor 2(Nrf2), and acetylcholinesterase (AchE) mRNA gene expression. The serum levels of CAT and SOD were (p < 0.0001; p < 0.0001) reduced in the SB only-treated group compared to the other groups. Nrf2 gene expression was totally shut down in the SB only-treated group but, up-regulated in the Zn-treated groups (p < 0.0001). The serum level of IL-1B was higher in the SB only-treated group compared to the other groups. SB-treated group spent longer time in the close arm (p = <0.0001), shorter time in the open arm (p = <0.0001) and had higher anxiety index (p = 0.0045) than the Zn-treated groups. Conclusively, Zinc improves memory deficit, has anxiolytic, anti-oxidant and anti-inflammatory properties.


Assuntos
Fator 2 Relacionado a NF-E2 , Síndromes Neurotóxicas , Animais , Masculino , Ratos , Ratos Wistar , Fator 2 Relacionado a NF-E2/metabolismo , Benzoato de Sódio/farmacologia , Acetilcolinesterase/metabolismo , Sulfato de Zinco , Memória de Curto Prazo , Regulação para Cima , Estresse Oxidativo , Superóxido Dismutase/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Zinco/farmacologia , Zinco/metabolismo
2.
J Ethnopharmacol ; 301: 115758, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36167232

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: As a traditional medicine, seeds of Ginkgo biloba L. (Gbs) have been used to treat cough or asthma for a long time. It is commonly used in clinic for lung diseases. However, its mechanism of lung protection is not completely clear. AIMS OF THE STUDY: This research was designed to explore the protective effects of Gbs on antioxidant and inflammation during the chronic obstructive pulmonary disease (COPD) pathological process provoked by cigarette smoking (CS) in rats. MATERIALS AND METHODS: Six random groups including control group, CS model group, Gbs intervention groups (25 mg/kg, 50 mg/kg, and 100 mg/kg) and aminophylline group were composed of forty-eight rats. Smoking and intratracheal instillation of lipopolysaccharide (LPS) were used to establish the COPD rat model. Glutathione peroxidase (GSH-PX), malondialdehyde (MDA), superoxide dismutase (SOD), and enzyme-linked immunosorbent assay (ELISA) was used for quantifying the inflammatory factors such as IL-8, IL-6, IL-10, IL-17 and TNF-α. Western blotting were used for detecting the protein expressions of Nrf2, Keap1 and HO-1 in the lung tissues. RESULTS: Gbs inhibits lung histological changes and decreased the inflammatory factors in both bronchoalveolar lavage fluid (BALF) and serum of CS-exposed rats, including IL-10, IL-17, IL-6, IL-8 and TNF-α. Gbs also inhibited the MDA level, increased SOD and GSH-PX activity in serum and changed expressions of Nrf2, Keap1 and HO-1 in the lung tissues. CONCLUSION: Gbs inhibit oxidative stress and inflammation induced by cigarette smoke in COPD rats through the Nrf2 Pathway.


Assuntos
Fumar Cigarros , Doença Pulmonar Obstrutiva Crônica , Animais , Ratos , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Antioxidantes/metabolismo , Fumar Cigarros/efeitos adversos , Ginkgo biloba , Inflamação/patologia , Interleucina-10/metabolismo , Interleucina-17/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Pulmão , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Sementes/metabolismo , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
3.
J Ethnopharmacol ; 301: 115777, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36191663

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Kunling Wan (KW) is a traditional Chinese medicine that is principally used for kidney deficiency, qi stagnation, and blood stasis, which are basic syndromes of infertility in China. KW can improve ovarian follicular development, ovarian function, and endometrial receptivity, which lead to improving pregnancy outcomes. Repeated controlled ovarian hyperstimulation (COH) reduces oocyte quality and results in a lower pregnancy rate. Whether KW has the potential to improve oocyte quality reduced by repeated COH has yet to be determined. AIMS OF THE STUDY: The aim of this study wwas to evaluate the effect of KW on oocyte quality after damage due to repeated COH, and to investigate the mechanism(s) underlying the antioxidative protection of oocytes by mitochondria. MATERIALS AND METHODS: Female Kunming mice were randomly divided into four groups: normal group, model (repeated COH) group, KW group, and N-acetylcysteine (NAC) group. We observed the morphology and quality of mitochondria, level of reactive oxygen species (ROS), and antioxidant enzymes activity of each group. Oocytes were treated with H2O2 and KW-containing serum, and we determined the antioxidant effects of KW on H2O2-treated oocytes and the mechanism involved in the regulation of Nrf2 in reducing oxidative damage. RESULTS: Our results revealed that repeated COH caused oxidative damage and impaired oocyte mitochondrial function and structure, resulting in poor oocyte quality. KW pretreatment reduced oxidative damage by inhibiting ROS production and improving mitochondrial structure and function, thereby enhancing overall oocyte quality. In response to H2O2, KW activated the PKC/Keap1/Nrf2-signaling pathway and promoted the translocation of Nrf2 from the cytoplasm to the nucleus, which activated the expression of SOD and GSH-Px, and removed the excess ROS that caused the initial mitochondrial damage. CONCLUSIONS: KW improved oocyte quality perturbed by repeated COH via reducing oxidative effects and improving mitochondrial function. The mechanism may be related to regulation of the PKC/Keap1/Nrf2 pathway in removing excess ROS.


Assuntos
Peróxido de Hidrogênio , Fator 2 Relacionado a NF-E2 , Animais , Feminino , Camundongos , Gravidez , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Peróxido de Hidrogênio/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Oócitos/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo
4.
J Ethnopharmacol ; 301: 115839, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36272490

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Xinfeng capsule is a traditional Chinese medicine compound, which has been clinically used for more than 20 years in the treatment of rheumatoid arthritis (RA), ankylosing spondylitis, osteoarthritis and its extracurricular lesions. However, the molecular role of XFC in the treatment of RA remains unclear. OBJECTIVE: This study aims to explore the efficacy and potential mechanism of XFC through retrospective data mining analysis, animal experiments and cell experiments. METHODS: The effect of XFC on clinical laboratory indexes of RA patients was observed using data mining techniques combined with association rule analysis and a random walk model. Afterwards, a rat model of adjuvant arthritis (AA) was established with Freund's complete adjuvant, followed by the observation of pathological changes in synovial tissues and the ultrastructure of synoviocytes. A RA cell model was constructed by inducing fibroblast-like synoviocytes (FLSs) with tumor necrosis factor-alpha (TNF-α) to assess the effects of XFC-containing serum on inflammation and oxidative stress through long non-coding RNA LINC00638. RESULTS: In retrospective data mining, XFC effectively reduced immune inflammation and increase the level of antioxidant enzymes in RA patients. Subsequently, animal experiments showed that XFC significantly repressed immune inflammation, oxidative stress, synovial hyperplasia, and cartilage destruction, while improving the ultrastructure of synoviocytes in AA rats. XFC-containing serum diminished the proliferation of TNF-α-induced RA-FLSs, increased LINC00638 expression (P<0.01), decreased interleukin-6 (IL-6), IL-17, reactive oxygen species (ROS) and reactive nitrogen species (RNS) levels (P<0.01), and increased the protein expression of nuclear factor erythrocyte 2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), and superoxide dismutase 2 (SOD2) (P<0.01). Furthermore, rescue experiments manifested that XFC-containing serum reversed the effects of silencing LINC00638 on inflammation and oxidative stress in RA-FLSs. CONCLUSION: XFC inhibits inflammation and oxidative stress in RA by up-regulating LINC00638 and activating Nrf2/HO-1 pathway.


Assuntos
Artrite Experimental , Artrite Reumatoide , Sinoviócitos , Animais , Ratos , Artrite Experimental/metabolismo , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/tratamento farmacológico , Heme Oxigenase-1/metabolismo , Inflamação/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Estudos Retrospectivos , Fator de Necrose Tumoral alfa/metabolismo , RNA Longo não Codificante
5.
J Ethnopharmacol ; 301: 115826, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36228893

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Xiehuo Xiaoying decoction (XHXY) has shown great potential in the treatment of GD, but its mechanism remains obscure. Increase of follicular helper T (Tfh) cells and reduction of follicular regulatory T (Tfr) cells contribute to a high thyrotropin receptor antibodies (TRAb) level and possible Graves' disease (GD). Oxidative stress (OS) disrupts T helper cell differentiation and aggravates autoimmunity. AIM OF THE STUDY: This study aimed to investigate whether XHXY decoction can ameliorate autoimmunity in GD via inhibiting OS and regulating Tfh and Tfr cells. MATERIALS AND METHODS: The main XHXY bioactive compounds were identified using high-performance liquid chromatography quadrupole time-of-flight mass spectrometry. GD was induced in the mice through three intramuscular injections of adenovirus expressing the TSH receptor. Then, the mice received oral gavage of XHXY (17 g/kg·d) and 34 g/kg·d) for 4 weeks. OS indicators were assessed. Flow cytometry was used to confirm the proportion of Tfh and Tfr cells in the lymph nodes and spleens of the mice. Cytokine expression levels were determined using enzyme-linked immunosorbent assay. Factors including interleukin-21, B-cell lymphoma-6, and forkhead box P3 (Foxp3) were detected using quantitative polymerase chain reaction. The mRNA and protein expression levels of Kelch-like ECH-associated protein 1 (Keap1), nuclear factor erythroid-2-related factor 2 (Nrf2), and haem oxygenase 1 (HO-1) were detected using quantitative polymerase chain reaction and Western blotting, respectively. RESULTS: Twelve main ingredients of XHXY were identified. XHXY relieved GD by lowering thyroxine (p < 0.01) and TRAb levels (p < 0.01). XHXY ameliorated OS by decreasing the levels of NADPH oxidase 2 (p < 0.05), 4-hydroxynonenal (p < 0.01), and 8-oxo-2'-deoxyguanosine (p < 0.001). It inhibited Tfh cell expansion (p < 0.05), as well as the production of cytokine interleukin -21 (p < 0.01), interleukin -4 (p < 0.01) and transcription factor B-cell lymphoma 6 (p < 0.05). XHXY also induced Tfr cell amplification (p < 0.05), increased the production of interleukin -10 (p < 0.05) and transforming growth factor ß (p < 0.05) and the mRNA levels of Foxp3 (p < 0.05). Finally, the Tfh/Tfr ratio returned to normal. In addition, XHXY activated Nrf2 and HO-1 expression, but inhibited Keap1 activation. CONCLUSIONS: XHXY relieves autoimmunity in GD via inhibiting Tfh cell amplification and Tfr cell reduction, a mechanism which probably involves the Keap1/Nrf2 signaling pathway.


Assuntos
Doença de Graves , Linfoma de Células B , Animais , Camundongos , Citocinas/metabolismo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Doença de Graves/tratamento farmacológico , Doença de Graves/metabolismo , Interleucinas/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Linfoma de Células B/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , RNA Mensageiro/metabolismo , Células T Auxiliares Foliculares , Linfócitos T Auxiliares-Indutores , Linfócitos T Reguladores , Medicina Tradicional Chinesa
6.
J Ethnopharmacol ; 301: 115824, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36273747

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Initially recorded in Yifang Jijie (an ancient Chinese text), Qi Gong Wan (QGW) is used to treat obese women with infertility. QGW can help promote follicular development and maturation, regulate the balance of serum hormones between testosterone and estradiol, enhance endometrial receptivity, improve waist circumference, and ameliorate insulin resistance. It contains eight herbs: Pinellia ternata (Thunb.) Makino (Banxia), Citrus maxima (Burm.) (Juhong), Poria cocos (Schw.) Wolf. (Fuling), Atractylodes macrocephala Koidz (Baizhu), Cyperus rotundus L. (Xiangfu), Conioselinum anthriscoides 'Chuanxiong' (Chuanxiong), Massa Medicata Fermentata (Shenqu), and Glycyrrhiza uralensis Fisch. ex DC. (Gancao). However, the underlying mechanism of how QGW affects women with PCOS remains unclear. AIM OF THE STUDY: QGW has been widely used to treat PCOS patients with obesity clinically. This study was designed to identify its chemical and pharmacological properties. MATERIALS AND METHODS: Network pharmacology was used to predict the active compounds, potential targets, and pathways of QGW. Female C57BL/6J mice were injected with letrozole and fed a high-fat diet to establish a PCOS-insulin resistance (PCOS-IR) model. Body weight, estrous cycles, ovarian pathology, and serum insulin resistance were measured. qRT-PCR was used to examine the inflammation-related and steroid hormone biosynthesis-related mRNA expression in adipose tissue. Western blotting was used to determine the protein levels of Nrf2, HO-1, and Cyp1b1 in adipose tissue. Molecular docking was used to reveal the key chemical compounds of QGW. RESULTS: Network pharmacology revealed a total of 91 active ingredients in QGW that were associated with 167 targets. QGW could potentially treat PCOS-IR via nitrogen metabolism, steroid hormone biosynthesis, and ovarian steroidogenesis pathways. In the PCOS-IR mouse model, we found that QGW decreased the mean diameter of adipocytes and the total adipocyte area. Furthermore, QGW was found to significantly lower the expression of inflammation-related genes including Tnfɑ and C4a/b and the steroid hormone biosynthesis-related gene Cyp1b1. QGW showed a tendency to improve cystic follicles, fasting insulin, and HOMA-IR index in the PCOS-IR mouse model. Combining these findings with the results of KEGG analysis, we conclude that QGW promotes the Nrf2/HO-1/Cyp1b1 pathway to protect adipose tissue under conditions of PCOS. Molecular docking revealed that rutin, nicotiflorin, and baicalein may be the key chemical compounds of QGW through which it improves adipocyte hypertrophy and inflammation. CONCLUSIONS: QGW improved adipocyte hypertrophy and inflammation in the PCOS-IR mouse model by activating the Nrf2/HO-1/Cyp1b1 pathway to protect adipose tissue. Our work thus provides a new research avenue for the study of traditional Chinese medicine in the treatment of PCOS.


Assuntos
Resistência à Insulina , Síndrome do Ovário Policístico , Qigong , Animais , Feminino , Humanos , Camundongos , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Modelos Animais de Doenças , Estradiol , Hipertrofia/patologia , Inflamação/metabolismo , Insulina , Resistência à Insulina/fisiologia , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Farmacologia em Rede , Fator 2 Relacionado a NF-E2/metabolismo , Obesidade/metabolismo , Síndrome do Ovário Policístico/tratamento farmacológico
7.
J Ethnopharmacol ; 301: 115776, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36191662

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Realgar, the main component of which is As2S2 or As4S4 (≥90%), is a traditional Chinese natural medicine that has been used to treat carbuncles, furuncles, snake and insect bites, abdominal pain caused by parasitic worms, and epilepsy in China for many years. Because realgar contains arsenic, chronic or excessive use of single-flavor realgar and realgar-containing Chinese patent medicine can lead to drug-induced arsenic poisoning, but the exact mechanism underlying its toxicity to the central nervous system is unclear. AIM OF THE STUDY: The aim of this study was to clarify the mechanism of realgar-induced neurotoxicity and to investigate the effects of realgar on autophagy and the Keap1-Nrf2-ARE pathway. MATERIALS AND METHODS: We used rats treated with the autophagy inhibitor 3-methyladenine (3-MA) or adeno-associated virus (AAV2/9-r-shRNA-Sqstm1, sh-p62) to investigate realgar-induced neurotoxicity and explore the specific relationship between autophagy and the Keap1-Nrf2-ARE pathway (the Nrf2 pathway) in the cerebral cortex. Molecular docking analysis was used to assess the interactions among the Nrf2, p62 and Keap1 proteins. RESULTS: Our results showed that arsenic from realgar accumulated in the brain and blood to cause neuronal and synaptic damage, decrease exploratory behavior and spontaneous movement, and impair memory ability in rats. The mechanism may have involved realgar-mediated autophagy impairment and continuous activation of the Nrf2 pathway via the LC3-p62-Keap1-Nrf2 axis. However, because this activation of the Nrf2 pathway was not sufficient to counteract oxidative damage, apoptosis was aggravated in the cerebral cortex. CONCLUSIONS: This study revealed that autophagy, the Nrf2 pathway, and apoptosis are involved in realgar-induced central nervous system toxicity and identified p62 as the hub of the LC3-p62-Keap1-Nrf2 axis in the regulation of autophagy, the Nrf2 pathway, and apoptosis.


Assuntos
Arsênio , Fator 2 Relacionado a NF-E2 , Animais , Ratos , Autofagia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Simulação de Acoplamento Molecular , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Proteína Sequestossoma-1/genética , Proteína Sequestossoma-1/metabolismo , Transdução de Sinais
8.
J Ethnopharmacol ; 301: 115765, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36195303

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Mesua Assamica (King & prain) Kosterm. (MA) is an evergreen endemic medicinal tree available in Assam in India and other parts of south Asia. The bark of the plant is traditionally used for ant-malarial activity and treating fevers. It was reported to have anti-oxidant, anti-inflammatory, anti-diabetic, anti-cancer and anti-malarial properties, but no research findings have been reported about its protective activity on intestinal inflammatory disorders like ulcerative colitis (UC) yet. AIM OF THE STUDY: The aim of the current study is to evaluate the anti-ulcerative property of ethanolic extract of MA (MAE) in-vitro on GloResponse™ NF-кB-RE-luc2P HEK 293 cells for its anti-oxidant and anti-inflammatory activities and in-vivo chronic restraint stress aggravated dextran sodium sulfate (DSS)-induced UC model. MATERIALS AND METHODS: The chemical constituents of MAE were identified by LC-MS/MS. The in-vitro effects of MAE on GloResponse™ NF-кB-RE-luc2P HEK 293 cells stimulated with TNF-α 30 ng/ml were investigated for its potential therapeutic effects. Parameters such as body weights, behavioural, colonoscopy, colon lengths and spleen weights were measured and recorded in chronic restraint stress aggravated DSS-induced UC model in C57BL/6 mice. Histological, cytokines and immunoblotting analysis in the colon tissues were determined to prove its anti-inflammatory and anti-oxidant activities. RESULTS: MAE poses significant anti-oxidant and anti-inflammatory activity in-vitro in GloResponse™ NF-кB-RE-luc2P HEK 293 cells evidenced by DCFDA and immunoflourescence assay. MAE treatment at 100 mg/kg and 200 mg/kg for 14 consecutive days has reduced Disease activity Index (DAI), splenomegaly and improved the shortened colon length and sucrose preference in mice. MAE treatment has increased the levels of anti-oxidants like GSH and reduced the levels of MDA, MPO and nitrite levels in colon tissues. Moreover, MAE has ameliorated neutrophil accumulation, mucosal and submucosal inflammation and crypt density evidenced by histopathology. Furthermore, MAE treatment significantly reduced the increased pro-inflammatory cytokines like IL-6, IL-1ß and TNF-α. we found from immunoblotting that there is a concomitant decrease in protein expression of NF-κB, STAT3 signalling cascades and phosphorylation of IKBα with an increase in Nrf2, SOD2, HO-1 and SIRT1 in colon tissues. In addition, we have performed molecular docking studies confirming that phytochemicals present in the MAE have a stronger binding ability and druggability to the NF-κB, Nrf2 and SIRT1 proteins. CONCLUSIONS: MAE exhibited significant anti-colitis activity on chronic restraint stress aggravated DSS-induced ulcerative colitis via regulating NF-κB/STAT3 and HO-1/Nrf2/SIRT1 signaling pathways.


Assuntos
Colite Ulcerativa , NF-kappa B , Animais , Humanos , Camundongos , Anti-Inflamatórios , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Antioxidantes/metabolismo , Cromatografia Líquida , Colite Ulcerativa/induzido quimicamente , Colo , Citocinas/metabolismo , Sulfato de Dextrana , Células HEK293 , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Casca de Planta/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Extratos Vegetais/metabolismo , Transdução de Sinais , Sirtuína 1/metabolismo , Espectrometria de Massas em Tandem , Fator de Necrose Tumoral alfa/metabolismo
9.
Theriogenology ; 195: 103-114, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36332369

RESUMO

Oxidative stress is a common cause of male infertility. Sertoli cells are one of the target cells of oxidative injury, which leads to impaired testicular function. Follicle-stimulating hormone (FSH) is critical in Sertoli cell function. However, the role of FSH in the response of goat Sertoli cells to H2O2-induced oxidative stress has not been studied yet. To investigate this response, we established an oxidative stress model using goat Sertoli cells. FSH pretreatment significantly enhanced the decreased cell viability (p < 0.05) caused by oxidative injury and inhibited autophagic flux. FSH significantly increased p62 mRNA and protein levels (p < 0.01). Further investigations revealed that FSH also increased the expression level and nuclear translocation of Nrf2 in Sertoli cells (p < 0.01), which resulted in increased antioxidant enzyme activity (p < 0.05). In contrast, treatment with siNrf2 and sip62 abolished this protective effect of FSH. These findings suggest that FSH protects Sertoli cells against oxidative stress via the p62-Nrf2 pathway, and that p62 accumulation maintains persistent activation of Nrf2. Thus, p62 and Nrf2 are required for FSH-mediated protective role in H2O2-induced Sertoli cell injury. The findings reveal new mechanisms by which FSH protects against oxidative injury in goat Sertoli cells.


Assuntos
Fator 2 Relacionado a NF-E2 , Células de Sertoli , Masculino , Animais , Fator 2 Relacionado a NF-E2/genética , Hormônio Foliculoestimulante/farmacologia , Cabras , Peróxido de Hidrogênio/toxicidade , Estresse Oxidativo , Autofagia , Antioxidantes
10.
Artigo em Inglês | MEDLINE | ID: mdl-36368504

RESUMO

Di (2-ethylhexyl) phthalate (DEHP) is often used as a plasticizer for plastic products, and its excessive use can cause irreversible damage to aquatic animals and humans. Evodiamine (EVO) is an alkaloid component in the fruit of Evodia rutaecarpa, which has antioxidant and detoxification functions. To investigate the toxic mechanism of DEHP on grass carp (Ctenopharyngodon idellus) hepatocyte cell line (L8824) and the therapeutic effect of evodiamine, an experimental model of L8824 cells exposed to 800 µM DEHP and/or 10 µM EVO for 24 h was established. Flow cytometry, AO/EB fluorescence staining, real-time quantitative PCR, and western blot were used to detect the degree of cell injury, oxidative stress level, MAPK signaling pathway relative genes, and the expression of apoptosis-related molecules. The results showed that DEHP exposure could significantly increase the level of reactive oxygen species (ROS), inhibit the activities of antioxidant enzymes (CAT, SOD, GSH-Px), and cause the accumulation of MDA. DEHP also activated MAPK signaling pathway-related molecules (JNK, ERK, P38 MAPK), and then up-regulated the expression of pro-apoptotic factors Bcl-2-Associated X (Bax) and caspase 3, while inhibiting the anti-apoptotic factor B-cell lymphoma-2 (Bcl-2). In addition, EVO can also promote the dissociation of nuclear factor-E2-related factor 2 (Nrf2) into the nucleus, reduce the level of ROS and the occurrence of oxidative stress in grass carp hepatocytes, down-regulate the MAPK pathway, alleviate DEHP-induced apoptosis, and restore the expression of antioxidant genes. These results indicated that evodiamine could block Nrf2/MAPK pathway to inhibit DEHP-induced apoptosis of grass carp hepatocytes.


Assuntos
Carpas , Dietilexilftalato , Animais , Humanos , Fator 2 Relacionado a NF-E2/genética , Dietilexilftalato/toxicidade , Espécies Reativas de Oxigênio , Antioxidantes/farmacologia , Hepatócitos , Apoptose , Proteínas Proto-Oncogênicas c-bcl-2
11.
Artigo em Inglês | MEDLINE | ID: mdl-36368507

RESUMO

Deltamethrin (Del) has been widely used for effectively controlling ectoparasites of crucian carp and was also strictly prohibited in a hypoxic environment. A previous study indicated that Del exposure causes gill injury in Carassius auratus, which is associated with oxidative stress and endoplasmic reticulum stress (ER stress), but the precise mechanism is not well understood. Here, crucian carp were exposed to Del (0.61, 1.22, 2.44, 4.88 µg/L) for 24 h and then subjected to acute hypoxia challenge (1.0 mg/L) for 24 h. The results revealed that acute exposure to Del notably increased MDA content but markedly decreased CAT activities. Moreover, the T-AOC and SOD activities first increased and then decreased in the 4.88 µg/L Del group. Likewise, the mRNA levels of Nrf2 signaling and its target genes (ho-1, mt, sod, cat, and gpx1) were significantly downregulated in the high concentration exposure groups, while the mRNA levels of keap1 showed the opposite change trend. Meanwhile, Del exposure evoked the PERK-ATF4-CHOP and IRE1 signaling pathways and triggered ER stress in a dose-dependent manner in crucian carp. Importantly, we found that Del exposure significantly decreased the survival rate of crucian carp after hypoxia challenge by reducing oxygen uptake, modifying energy metabolism, and promoting lactate accumulation. Additionally, Del exposure aggravated gill damage and apoptosis under hypoxic stress, which was confirmed by histological assays. Collectively, we inferred that acute exposure to deltamethrin induces oxidative stress and ER stress and impairs hypoxic resistance of crucian carp.


Assuntos
Carpas , Estresse do Retículo Endoplasmático , Animais , Proteína 1 Associada a ECH Semelhante a Kelch , Fator 2 Relacionado a NF-E2 , Hipóxia , Estresse Oxidativo , RNA Mensageiro , Superóxido Dismutase
12.
J Hazard Mater ; 441: 129872, 2023 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-36084461

RESUMO

Decabromodiphenyl ethane (DBDPE), a new brominated flame retardant, could negatively affect neurobehavior and pose health risks to humans. Humans are also exposed to widely used nanomaterials. This study investigated the combined toxic effects and action types of DBDPE and Zinc oxide nanoparticles (ZnO NPs) on human neuroblastoma SK-N-SH cells and the toxicity mechanisms. DBDPE inhibited the viability of SK-N-SH cells by 21.87% at 25 mg/L. ZnO NPs synergistically exacerbated the toxic effects of DBDPE. DBDPE and ZnO NPs caused excessive ROS production and inhibition of antioxidant enzyme (SOD and GSH) activity in cells, thus causing oxidative cellular damage. Moreover, DBDPE and ZnO NPs caused apoptosis by disrupting mitochondrial kinetic homeostasis, reducing mitochondrial membrane potential (MMP), increasing cytochrome C release and regulating Bax/Bcl-2 and Caspase-3 mRNA and protein expression. DBDPE and ZnO NPs increased the mRNA expression of nuclear factor erythroid 2- related factor (Nrf2) and its downstream genes. The molecular mechanisms revealed that oxidative stress, apoptosis and mitochondrial dysfunction were the critical factors in combined cytotoxicity. The bioinformatics analysis further indicated that co-exposure affected Nrf2 activation, apoptotic factors expression and mitochondrial fusion. The findings enrich the risk perception of neurotoxicity caused by DBDPE and ZnO NPs.


Assuntos
Retardadores de Chama , Nanopartículas , Óxido de Zinco , Antioxidantes/metabolismo , Apoptose , Caspase 3/metabolismo , Citocromos c/metabolismo , Retardadores de Chama/metabolismo , Humanos , Mitocôndrias , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Nanopartículas/toxicidade , Estresse Oxidativo , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Superóxido Dismutase/metabolismo , Óxido de Zinco/toxicidade , Proteína X Associada a bcl-2/metabolismo , Proteína X Associada a bcl-2/farmacologia
13.
J Ethnopharmacol ; 301: 115775, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36198377

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Palmatine (Pal) is a major bioactive alkaloid originated from ancient Chinese herbal medicine Cortex Phellodendri Amurensis (CPA), which has long been applied to treat hyperuricemia (HUA)-related diseases. Pal possesses potent anti-inflammatory and anti-oxidant effects against metabolic diseases. However, its potential beneficial effect against PO (potassium oxonate)/HX (hypoxanthine)-induced HUA remains elusive. AIM OF THE STUDY: This study aimed to investigate the potential pharmacological effect and mechanism of Pal on PO/HX-induced HUA in mice. MATERIAL AND METHODS: A mouse model of HUA was established by co-administration of PO/HX once daily for 7 consecutive days. The HUA mice were orally given three doses (25, 50 and 100 mg/kg) of Pal daily for a week. Febuxostat (Feb, 5 mg/kg) was given as a positive control. At the scheduled termination of the experiment, the whole blood, liver and kidney were collected for subsequent analyses. The concentrations of uric acid (UA), creatinine (CRE) and blood urea nitrogen (BUN), and activities of adenosine deaminase (ADA) and xanthine oxidase (XOD) were evaluated. Histopathological alterations of the kidney were detected by H&E staining. The inflammatory and oxidative stress status was detected by assay kits. Additionally, key proteins involved in the urate transporter, Keap1-Nrf2 and TXNIP/NLRP3 signaling pathways were evaluated by immunohistochemistry and Western blotting. Finally, molecular docking was employed to probe the binding characteristics of Pal and target proteins Keap1, NLRP3, URAT1 and HO-1. RESULTS: Administration of Pal substantially decreased the elevated kidney weight, lowered UA, CRE and BUN levels, and attenuated abnormal histopathological alterations. Meanwhile, treatment with Pal also dramatically lowered hepatic XOD and ADA activities. Besides, Pal treatment effectively mitigated the renal inflammatory and oxidative stress markers. Further mechanistic investigation indicated Pal distinctly downregulated the protein levels of GLUT9 and URAT1, while up-regulated the expression levels of OAT1 and ABCG2. Pal also restored Nrf2 activation, promoted subsequent expression of anti-oxidative enzymes, and downregulated the expressions of TXNIP, NLRP3, apoptosis-associated speck-like (ASC), caspase-1, IL-1ß and IL-18. Molecular docking analysis also indicated Pal firmly bound with Keap1, NLRP3, URAT1 and HO-1. CONCLUSIONS: These findings indicated that Pal exhibited favorable anti-HUA effect via modulating the expressions of transporter-related proteins and suppressing XOD activity. Furthermore, Pal also alleviated HUA-induced kidney injury, which was at least partially related to restoring Keap1-Nrf2 pathway and inhibiting TXNIP/NLRP3 inflammasome. Our investigation was envisaged to provide experimental support for the traditional application of CPA and CPA-containing classical herbal formulas in the management of HUA-related diseases and might provide novel dimension to the clinical application of Pal.


Assuntos
Hiperuricemia , Ácido Úrico , Camundongos , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Simulação de Acoplamento Molecular , Hiperuricemia/induzido quimicamente , Hiperuricemia/tratamento farmacológico , Hiperuricemia/metabolismo , Xantina Oxidase/metabolismo , Rim , Creatinina
14.
J Surg Res ; 281: 245-255, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36209683

RESUMO

INTRODUCTION: Heme oxygenase-1 (HO-1) is a protective protein in oxidative stress response. LXA4 is an "inflammatory braking signal" that is widely studied at present. The purpose of this study was to elucidate that LXA4 can protect cells by inducing HO-1 in human pulmonary microvascular endothelial cells (HPMECs) as in vitro model to explain acute lung injury after severe acute pancreatitis. METHODS: This study was performed in two parts: (1) To investigate the mechanisms of lipoxin A4-induced HO-1 expression in vitro, the study subjects were divided into four groups: a control group, LXA4 group (50 ng/mL LXA4), inhibitor group (50 ng/mL LXA4 + 20 µM LY294002 or 50 ng/mL LXA4 + 2 nmol/mL Bis II), and agonist group (50 ng/mL insulin-like growth factor 1, PMA). Western blotting was used to detect the expression of p-Akt, Akt, protein kinase C (PKC), p-Nrf2, Nrf2, and Keap1, and the location of Nrf2 was detected using immunofluorescence. The activation of antioxidant responsive element induced by Nrf2 was detected using Electrophoretic Mobility Shift Assay and (2) to investigate the cytoprotection of HO-1 induced by LXA4 in vitro, the subjects were divided into four groups: a control group, tumor necrosis factor α (TNF-α) group (50 ng/mL), LXA4 group (50 ng/mL TNF-α + 50 ng/mL LXA4), and Zinc protoporphyrin IX group (pretreated with 0.5 µM Zinc protoporphyrin IXfor 12 h, followed by 50 ng/mL TNF-α + 50 ng/mL LXA4). BCECF/AM-labeled THP-1 cells were used to analyze the adhesion of HPMECs, and a mitochondrial membrane potential assay kit with JC-1 was used to analyze the apoptosis of HPMECs. RESULTS: In part one, (1) LXA4 upregulated the expression of HO-1 in a dose-dependent manner and (2) LXA4 activated the PI3K/Akt and PKC pathways and modulated the phosphorylation and subsequent depolymerization of Nrf2 from Keap1, promoting the translocation of Nrf2 to the nucleus. In part two, (1) LXA4 reversed the changes in mitochondrial membrane potential to alleviate apoptosis in HPMECs and (2) LXA4 attenuated the adhesion of HPMECs induced by TNF-α. CONCLUSIONS: LXA4 can activate the PI3K/Akt and PKC pathways and induce the phosphorylation of Nrf2, resulting in the upregulation of HO-1. In addition, LXA4 alleviates adhesion and protects mitochondrial function by upregulating the expression of HO-1, which exerts cytoprotection in severe acute pancreatitis-induced lung injury.


Assuntos
Lesão Pulmonar Aguda , Pancreatite , Humanos , Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Citoproteção , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Doença Aguda , Células Endoteliais/metabolismo , Estresse Oxidativo , Lesão Pulmonar Aguda/prevenção & controle
15.
Mol Med Rep ; 27(1)2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36321783

RESUMO

Allergic asthma is a chronic inflammatory disease in which oxidative stress serves a pivotal role. In clinical practice, dexmedetomidine (DEX), an α­2­adrenergic receptor agonist, is used as a sedative. DEX exhibits antioxidative and organ­protective properties. In a murine model of asthma, DEX has a therapeutic effect via the toll like receptor 4/NF­ÐºB signaling pathway; however, whether DEX can exert an antioxidative effect on asthma has yet to be elucidated. In the present study, a T helper (Th)2­dominant murine asthma model was established. DEX treatment significantly reduced eosinophilic airway inflammation, mucus overproduction and airway hyperresponsiveness, as well as the concentrations of Th2 cytokines. The lung tissues of mice with asthma were characterized by redox imbalance (increased oxidative stress and impaired antioxidant capacity). DEX treatment alleviated this imbalance by decreasing the levels of malondialdehyde and reactive oxygen species, and increasing the levels of glutathione. Furthermore, the nuclear factor erythroid 2­related factor 2 (Nrf2) signaling pathway was inhibited in the lung tissues of asthmatic mice; these effects were noted in its downstream genes, heme oxygenase 1 and glutathione peroxidase 4. In mice with asthma, DEX treatment induced the expression of these antioxidant genes and the activation of Nrf2, whereas ML385 (an inhibitor of Nrf2) partially abrogated the antioxidative and therapeutic effects of DEX. To the best of our knowledge, the present study is the first to demonstrate the protective effect of DEX on Th2­dominant asthma through the activation of the Nrf2 signaling pathway. The results suggested that the antioxidative properties of DEX could be beneficial in clinical application of DEX for the relief of asthmatic symptoms.


Assuntos
Asma , Dexmedetomidina , Camundongos , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Dexmedetomidina/farmacologia , Antioxidantes/farmacologia , Estresse Oxidativo , Asma/metabolismo , Inflamação/metabolismo , Transdução de Sinais , Fator de Transcrição de Proteínas de Ligação GA/metabolismo
16.
Oxid Med Cell Longev ; 2022: 4564471, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35308167

RESUMO

The polarization of microglia is recognized as a crucial factor in reducing neuroinflammation and promoting hematoma clearance after intracerebral hemorrhage (ICH). Previous studies have revealed that redox components participate in the regulation of microglial polarization. Recently, the novel Nrf2 activator omaveloxolone (Omav) has been validated to improve neurological function in patients with neurodegenerative disorders by regulating antioxidant responses. In this study, we examined the efficacy of Omav in ICH. Omav significantly promoted Nrf2 nuclear accumulation and the expression of HO-1 and NQO1 in BV2 cells. In addition, both in vitro and in vivo experiments showed that Omav treatment inhibited M1-like activation and promoted the activation of the M2-like microglial phenotype. Omav inhibited OxyHb-induced ROS generation and preserved the function of mitochondria in BV2 cells. Intraperitoneal administration of Omav improved sensorimotor function in the ICH mouse model. Importantly, these effects were blocked by pretreatment with ML385, a selective inhibitor of Nrf2. Collectively, Omav modulated microglial polarization by activating Nrf2 and inhibiting ROS generation in ICH models, suggesting that it might be a promising drug candidate for the treatment of ICH.


Assuntos
Lesões Encefálicas , Microglia , Animais , Lesões Encefálicas/tratamento farmacológico , Hemorragia Cerebral/complicações , Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/metabolismo , Humanos , Camundongos , Microglia/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fenótipo , Triterpenos
17.
Matrix Biol ; 113: 39-60, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36367485

RESUMO

Aging is associated with progressive skin fragility and a tendency to tear, which can lead to severe clinical complications. The transcription factor NRF2 is a key regulator of the cellular antioxidant response, and pharmacological NRF2 activation is a promising strategy for the prevention of age-related diseases. Using a combination of molecular and cellular biology, histology, imaging and biomechanical studies we show, however, that constitutive genetic activation of Nrf2 in fibroblasts of mice suppresses collagen and elastin expression, resulting in reduced skin strength as seen in aged mice. Mechanistically, the "aging matrisome" results in part from direct Nrf2-mediated overexpression of a network of microRNAs that target mRNAs of major skin collagens and other matrix components. Bioinformatics and functional studies revealed high NRF2 activity in aged human fibroblasts in 3D skin equivalents and human skin biopsies, highlighting the translational relevance of the functional mouse data. Together, these results identify activated NRF2 as a promoter of age-related molecular and biomechanical skin features.


Assuntos
MicroRNAs , Envelhecimento da Pele , Humanos , Camundongos , Animais , Idoso , Envelhecimento da Pele/genética , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Fibroblastos/metabolismo , Colágeno/genética , Colágeno/metabolismo , Pele/metabolismo , Fenótipo
18.
Cell Rep ; 41(6): 111610, 2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36351395

RESUMO

In both humans and mice, repair of acute kidney injury is worse in males than in females. Here, we provide evidence that this sexual dimorphism results from sex differences in ferroptosis, an iron-dependent, lipid-peroxidation-driven regulated cell death. Using genetic and single-cell transcriptomic approaches in mice, we report that female sex confers striking protection against ferroptosis, which was experimentally induced in proximal tubular (PT) cells by deleting glutathione peroxidase 4 (Gpx4). Single-cell transcriptomic analyses further identify the NFE2-related factor 2 (NRF2) antioxidant protective pathway as a female resilience mechanism against ferroptosis. Genetic inhibition and pharmacological activation studies show that NRF2 controls PT cell fate and plasticity by regulating ferroptosis. Importantly, pharmacological NRF2 activation protects male PT cells from ferroptosis and improves cellular plasticity as in females. Our data highlight NRF2 as a potential therapeutic target to prevent failed renal repair after acute kidney injury in both sexes by modulating cellular plasticity.


Assuntos
Injúria Renal Aguda , Ferroptose , Humanos , Feminino , Masculino , Camundongos , Animais , Caracteres Sexuais , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Rim/metabolismo
19.
Transl Psychiatry ; 12(1): 459, 2022 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-36316319

RESUMO

The expression of the triggering receptor on myeloid cell-2 (TREM2) knockdown in microglia from the lateral habenula (LHb) reportedly induces depression-like behaviors in mice. However, the key molecular mechanism that mediates major depressive disorder (MDD) pathogenesis remains elusive. We herein show that Nrf2 regulates TREM2 transcription and effects TREM2 mRNA and protein expression. The activation of Nrf2 by sulforaphane (Nrf2 activator) increases the microglial arginase 1+ phenotype by initiating TREM2 transcription in the medial prefrontal cortex (mPFC) and ameliorates depression-like behavior in CSDS mice. The knockout of Nrf2 decreases TREM2 and the microglial arginase 1+ phenotype in the mPFC of Nrf2 KO mice with depression-like behavior. Downregulating TREM2 expression decreases the microglial arginase 1+ phenotype in the mPFC, resulting in depression-like behavior in SFN-treated CSDS mice. Finally, the knockout of Nrf2 and downregulation of TREM2 expression decreases the microglial arginase 1+ phenotype in the mPFC of Nrf2 KO mice and SFN-treated CSDS mice were associated with the brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling pathway. These data indicate that alterations in the interaction between Nrf2 and TREM2 may play a role in the pathophysiology of depression-like behavior in mice.


Assuntos
Transtorno Depressivo Maior , Microglia , Animais , Camundongos , Microglia/metabolismo , Fator 2 Relacionado a NF-E2/genética , Arginase/genética , Arginase/metabolismo , Depressão/tratamento farmacológico , Depressão/genética , Transtorno Depressivo Maior/metabolismo , Fenótipo , Camundongos Knockout , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Receptores Imunológicos/genética
20.
Molecules ; 27(21)2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36364301

RESUMO

The aim of the present study was to determine the major anthocyanins of blueberry extracts from northeast China and explore their vision health improvement effects. HPLC-Q-TOF-MS/MS results suggested that six different anthocyanins were accurately identified, among which the Cy-3-glu (C3G) was the most abundant, ranging from 376.91 ± 7.91 to 763.70 ± 4.99 µM. The blueberry extract contained a higher purity of anthocyanins, and the anthocyanosides reached 342.98 mg/kg. The anti-oxidative stress function of C3G on HG-treated ARPE-19 cells were evaluated, and showed that the GSSG level of HG-cells pretreated with 10 µM C3G was significantly decreased, while the Nrf2 and NQO1 gene expression levels were increased. Further molecular docking (MD) results indicated that the C3G displayed favorable binding affinity towards REDD1, and only the B-ring of the C3G molecule displayed binding interactions with the CYS-140 amino acids within the REDD1 protein. It implied that the oxidative stress amelioration effects of C3G on the ARPE-19 cells were related to the REDD1 protein, which was probably via the Nrf2 pathways, although further studies are needed to provide mechanism evidence. The present study provides novel insights into understanding the roles of blueberry anthocyanins in ameliorating oxidative stress-induced BRB damage in the retina.


Assuntos
Mirtilos Azuis (Planta) , Diabetes Mellitus , Retinopatia Diabética , Antocianinas/farmacologia , Mirtilos Azuis (Planta)/química , Fator 2 Relacionado a NF-E2/metabolismo , Glucosídeos/farmacologia , Simulação de Acoplamento Molecular , Espectrometria de Massas em Tandem
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