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1.
Sci Rep ; 14(1): 2973, 2024 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-38316940

RESUMO

The nuclear factor erythroid 2-related factor 2 (NRF2) is a crucial transcription factor that plays a central role in regulating oxidative stress pathways by binding antioxidant response elements, but its involvement in early embryo development remains largely unexplored. In this study, we demonstrated that NRF2 mRNA is expressed in porcine embryos from day 2 to day 7 of development, showing a decrease in abundance from day 2 to day 3, followed by an increase on day 5 and day 7. Comparable levels of NRF2 mRNA were observed between early-cleaving and more developmental competent embryos and late-cleaving and less developmental competent embryos on day 4 and day 5 of culture. Attenuation of NRF2 mRNA significantly decreased development of parthenote embryos to the blastocyst stage. When NRF2-attenuated embryos were cultured in presence of 3.5 mM or 7 mM glucose, development to the blastocyst stage was dramatically decreased in comparison to the control group (15.9% vs. 27.8% for 3.5 mM glucose, and 5.4% vs. 25.3% for 7 mM glucose). Supplementation of melatonin moderately improved the development of NRF2-attenuated embryos cultured in presence of 0.6 mM glucose. These findings highlight the importance of NRF2 in early embryo development, particularly in embryos cultured under metabolically stressful conditions.


Assuntos
Desenvolvimento Embrionário , Fator 2 Relacionado a NF-E2 , Suínos , Animais , Desenvolvimento Embrionário/genética , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Blastocisto/metabolismo , Glucose/metabolismo , Estresse Fisiológico , RNA Mensageiro/metabolismo , Técnicas de Cultura Embrionária
2.
Front Immunol ; 15: 1330678, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38322262

RESUMO

The damage to the central nervous system and dysfunction of the body caused by spinal cord injury (SCI) are extremely severe. The pathological process of SCI is accompanied by inflammation and injury to nerve cells. Current evidence suggests that oxidative stress, resulting from an increase in the production of reactive oxygen species (ROS) and an imbalance in its clearance, plays a significant role in the secondary damage during SCI. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial regulatory molecule for cellular redox. This review summarizes recent advancements in the regulation of ROS-Nrf2 signaling and focuses on the interaction between ROS and the regulation of different modes of neuronal cell death after SCI, such as apoptosis, autophagy, pyroptosis, and ferroptosis. Furthermore, we highlight the pathways through which materials science, including exosomes, hydrogels, and nanomaterials, can alleviate SCI by modulating ROS production and clearance. This review provides valuable insights and directions for reducing neuronal cell death and alleviating SCI through the regulation of ROS and oxidative stress.


Assuntos
Fator 2 Relacionado a NF-E2 , Traumatismos da Medula Espinal , Humanos , Espécies Reativas de Oxigênio/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Traumatismos da Medula Espinal/patologia , Apoptose , Estresse Oxidativo
3.
FASEB J ; 38(3): e23452, 2024 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-38308640

RESUMO

Autophagy is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). We aimed to investigate whether the p62-Keap1-Nrf2 pathway affects the development of PAH by mediating autophagy. A PAH rat model was established using monocrotaline (MCT). Pulmonary artery smooth muscle cells (PASMCs) were extracted, and the changes in proliferation, migration, autophagy, and oxidative stress were analyzed following overexpression or knockdown of p62. The impact of p62 on the symptoms of PAH rats was assessed by the injection of an adenovirus overexpressing p62. We found that the knockdown of p62 increased the proliferation and migration of PASMCs, elevating the oxidative stress of PASMCs and upregulating gene expression of NADPH oxidases. Co-IP assay results demonstrated that p62 interacted with Keap1. p62 knockdown enhanced Keap1 protein stability and Nrf2 ubiquitination. LC3II/I and ATG5 were expressed more often when p62 was knocked down. Treating with an inhibitor of autophagy reversed the impact of p62 knockdown on PASMCs. Nrf2 inhibitor treatment reduced the expression of Nrf2 and p62, while increasing the expression of Keap1, LC3II/I, and ATG5 in PASMCs. However, overexpressing p62 diminished mRVP, SPAP, and Fulton index in PAH rats and attenuated pulmonary vascular wall thickening. Overexpression of p62 also decreased the expression of Keap1, LC3II/I, and ATG5 and increased the nuclear expression of Nrf2 in PAH rats. Importantly, overexpression of p62 reduced oxidative stress and the NADPH oxidase expression in PAH rats. Overall, activation of the p62-Keap1-Nrf2 positive feedback signaling axis reduces the proliferation and migration of PASMCs and alleviates PAH by inhibiting autophagy and oxidative stress.


Assuntos
Hipertensão Arterial Pulmonar , Animais , Ratos , Autofagia/fisiologia , Proliferação de Células , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Monocrotalina , Miócitos de Músculo Liso/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Hipertensão Arterial Pulmonar/patologia , Artéria Pulmonar/metabolismo
4.
J Cardiothorac Surg ; 19(1): 58, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38317168

RESUMO

BACKGROUND: This study examined the effect of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway on chronic obstructive pulmonary disease (COPD) and the potential molecular mechanism. METHODS: A COPD mouse model was established by cigarette smoke exposure and administered with either ML385 or dimethyl fumarate (DMF). Airway resistance of mice was detected. IL-1ß and IL-6 levels in mice alveolar lavage fluid were examined by enzyme-linked immunosorbent assay. Hematoxylin and eosin staining and immunohistochemical of lung tissues were utilized to detect lung injury and NLRP3 expression. DMF was used to treat COPD cell model constructed by exposing normal human bronchial epithelial (NHBE) cells to cigarette smoke extract. NHBE cells were transfected by NLRP3-expression vectors. Expression of proteins was detected by Western blot. RESULTS: COPD mice showed the enhanced airway resistance, the inactivated Nrf2/HO-1 pathway and the overexpressed NLRP3, Caspase-1 and GSDMD-N proteins in lung tissues, and the increased IL-1ß and IL-6 levels in alveolar lavage fluid. ML385 treatment augmented these indicators and lung injury in COPD mice. However, DMF intervention attenuated these indicators and lung injury in COPD mice. Nrf2/HO-1 pathway inactivation and overexpression of NLRP3, Caspase-1 and GSDMD-N proteins were observed in COPD cells. DMF intervention activated Nrf2/HO-1 pathway and down-regulated NLRP3, Caspase-1 and GSDMD-N proteins in COPD cells. However, NLRP3 overexpression abolished the effect of DMF on COPD cells. CONCLUSION: Nrf2/HO-1 pathway activation may alleviate inflammation in COPD by suppressing the NLRP3-related pyroptosis. Activating the Nrf2/HO-1 pathway may be an effective method to treat COPD.


Assuntos
Fumar Cigarros , Lesão Pulmonar , Doença Pulmonar Obstrutiva Crônica , Humanos , Camundongos , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Piroptose , Interleucina-6 , Heme Oxigenase-1/metabolismo , Fumar Cigarros/efeitos adversos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Inflamação , Caspases
5.
J Nanobiotechnology ; 22(1): 48, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38302938

RESUMO

Inflammatory bowel disease (IBD) is closely linked to the homeostasis of the intestinal environment, and exosomes can be used to treat IBD due to their high biocompatibility and ability to be effectively absorbed by the intestinal tract. However, Ginseng-derived nanoparticles (GDNPs) have not been studied in this context and their mechanism of action remains unclear. Here, we investigated GDNPs ability to mediate intercellular communication in a complex inflammatory microenvironment in order to treat IBD. We found that GDNPs scavenge reactive oxygen species from immune cells and intestinal epithelial cells, inhibit the expression of pro-inflammatory factors, promote the proliferation and differentiation of intestinal stem cells, as well as enhancing the diversity of the intestinal flora. GDNPs significantly stabilise the intestinal barrier thereby promoting tissue repair. Overall, we proved that GDNPs can ameliorate inflammation and oxidative stress in vivo and in vitro, acting on the TLR4/MAPK and p62/Keap1/Nrf2 pathways, and exerting an anti-inflammatory and antioxidant effect. GDNPs mitigated IBD in mice by reducing inflammatory factors and improving the intestinal environment. This study offers new evidence of the potential therapeutic effects of GDNPs in the context of IBD, providing the conceptual ground for an alternative therapeutic strategy.


Assuntos
Doenças Inflamatórias Intestinais , Nanopartículas , Panax , Animais , Camundongos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Nanopartículas/uso terapêutico , Fator 2 Relacionado a NF-E2/metabolismo , Panax/metabolismo , Receptor 4 Toll-Like/metabolismo
6.
BMC Complement Med Ther ; 24(1): 71, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38303002

RESUMO

BACKGROUND: Melissa officinalis (MO) is a well-known medicinal plant species used in the treatment of several diseases; it is widely used as a vegetable, adding flavour to dishes. This study was designed to evaluate the therapeutic effect of MO Extract against hyperthyroidism induced by Eltroxin and γ-radiation. METHODS: Hyperthyroidism was induced by injecting rats with Eltroxin (100 µg/kg/ day) for 14 days and exposure to γ-radiation (IR) (5 Gy single dose). The hyperthyroid rats were orally treated with MO extract (75 mg/kg/day) at the beginning of the second week of the Eltroxin injection and continued for another week. The levels of thyroid hormones, liver enzymes and proteins besides the impaired hepatic redox status and antioxidant parameters were measured using commercial kits. The hepatic gene expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its inhibitor Kelch-like ECH-associated protein-1(Keap-1) in addition to hepatic inflammatory mediators including tumor necrosis factor-α (TNF- α), Monocyte chemoattractant protein-1 (MCP-1) and fibrogenic markers such as transforming growth factor-beta1 (TGF-ß1) were determined. RESULTS: MO Extract reversed the effect of Eltroxin + IR on rats and attenuated the thyroid hormones. Moreover, it alleviated hyperthyroidism-induced hepatic damage by inhibiting the hepatic enzymes' activities as well as enhancing the production of proteins concomitant with improving cellular redox homeostasis by attenuating the deranged redox balance and modulating the Nrf2/Keap-1 pathway. Additionally, MO Extract alleviated the inflammatory response by suppressing the TNF- α and MCP-1 and prevented hepatic fibrosis via Nrf2-mediated inhibition of the TGF-ß1/Smad pathway. CONCLUSION: Accordingly, these results might strengthen the hepatoprotective effect of MO Extract in a rat model of hyperthyroidism by regulating the Nrf-2/ Keap-1 pathway.


Assuntos
Hipertireoidismo , Hepatopatias , Melissa , Extratos Vegetais , Animais , Ratos , Expressão Gênica , Hipertireoidismo/complicações , Hipertireoidismo/tratamento farmacológico , Inflamação/metabolismo , Fígado , Melissa/química , Fator 2 Relacionado a NF-E2/metabolismo , Oxirredução , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Hormônios Tireóideos/metabolismo , Tiroxina/genética , Tiroxina/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Hepatopatias/etiologia , Hepatopatias/terapia
7.
Clin Exp Pharmacol Physiol ; 51(3): e13841, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38302077

RESUMO

The study aimed to investigate the harmful effects of acrylamide (AA), which forms in carbohydrate-rich foods at temperatures above 120°C, on the central and peripheral nervous systems and to evaluate the potential neuroprotective effects of carvacrol (CRV). Male Wistar Albino rats were subjected to AA (40 mg/kg/bw/day) and CRV (50 mg/kg/bw/day) for 15 days. Following the last administration, evaluations revealed disrupted gait, heightened thermal sensitivity and altered paw withdrawal thresholds in AA-exposed rats. Notably, AA reduced glutathione (GSH) and raised malondialdehyde (MDA) levels in both brain and sciatic nerve tissues. AA raised nuclear factor erythroid 2-related factor 2 (Nrf2), caspase 3 and nuclear factor κB (NF-κB) gene expressions while decreasing NR4A2. CRV co-administration mitigated gait abnormalities, elevated GSH levels and lowered MDA levels in both tissues. CRV also modulated gene expression, reducing Nrf2 and NF-κB while increasing NR4A2. Histopathological signs of AA-induced neurodegeneration and elevated glial fibrillary acidic protein levels observed in brain and sciatic nerve tissues were rectified with simultaneous administration of CRV, thereby demonstrating neuroprotective efficacy in both regions. This study is pioneering in demonstrating CRV's neuroprotective potential against AA-induced neurotoxicity in both central and peripheral nervous systems, effectively addressing limitations in the literature. In conclusion, the study revealed AA-induced neurodegeneration in the brain and sciatic nerve, with CRV significantly mitigating this neurotoxicity. This novel research underscores CRV's promise as a neuroprotective agent against AA-induced adverse effects in both the central and peripheral nervous systems.


Assuntos
Cimenos , Fármacos Neuroprotetores , Síndromes Neurotóxicas , Ratos , Masculino , Animais , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Ratos Wistar , Estresse Oxidativo , Acrilamida/toxicidade , NF-kappa B/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Antioxidantes/farmacologia , Nervo Isquiático/metabolismo , Síndromes Neurotóxicas/metabolismo , Encéfalo/metabolismo
8.
JCI Insight ; 9(3)2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38329125

RESUMO

Although cold preservation remains the gold standard in organ transplantation, cold stress-induced cellular injury is a significant problem in clinical orthotopic liver transplantation (OLT). Because a recent study showed that cold stress activates ferroptosis, a form of regulated cell death, we investigated whether and how ferroptosis determines OLT outcomes in mice and humans. Treatment with ferroptosis inhibitor (ferrostatin-1) during cold preservation reduced lipid peroxidation (malondialdehyde; MDA), primarily in liver sinusoidal endothelial cells (LSECs), and alleviated ischemia/reperfusion injury in mouse OLT. Similarly, ferrostatin-1 reduced cell death in cold-stressed LSEC cultures. LSECs deficient in nuclear factor erythroid 2-related factor 2 (NRF2), a critical regulator of ferroptosis, were susceptible to cold stress-induced cell death, concomitant with enhanced endoplasmic reticulum (ER) stress and expression of mitochondrial Ca2+ uptake regulator (MICU1). Indeed, supplementing MICU1 inhibitor reduced ER stress, MDA expression, and cell death in NRF2-deficient but not WT LSECs, suggesting NRF2 is a critical regulator of MICU1-mediated ferroptosis. Consistent with murine data, enhanced liver NRF2 expression reduced MDA levels, hepatocellular damage, and incidence of early allograft dysfunction in human OLT recipients. This translational study provides a clinically applicable strategy in which inhibition of ferroptosis during liver cold preservation mitigates OLT injury by protecting LSECs from peritransplant stress via an NRF2-regulatory mechanism.


Assuntos
Cicloexilaminas , Ferroptose , Transplante de Fígado , Fenilenodiaminas , Camundongos , Humanos , Animais , Transplante de Fígado/efeitos adversos , Células Endoteliais/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Resposta ao Choque Frio , Fígado/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo
9.
Nutrients ; 16(3)2024 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-38337735

RESUMO

Atopic dermatitis (AD) is a persistent inflammatory skin condition resulting from an intricate interplay among genetic, immunological, and environmental factors. Erigeron annuus (EA), an annual winter plant belonging to the family Asteraceae, possesses anti-inflammatory, cytoprotective, and antioxidant activities. In this study, we hypothesized that Erigeron annuus extract (EAE) could be an effective agent for ameliorating AD-like symptoms. To confirm this hypothesis in vitro, we used H2O2-stimulated human keratinocytes (HaCaT cells) to demonstrate that pre-treatment with EAE protected against oxidative stress. HaCaT cells pretreated with EAE and stimulated with H2O2 showed decreased intracellular malondialdehyde content, increased superoxide dismutase activity, and reduced intracellular reactive oxygen species accumulation. To verify the in vivo hypothesis based on the intracellular results, an AD disease mouse model was induced with 1-chloro-2,4-dinitrobenzene (DNCB), and EAE was orally administered at a non-toxic concentration according to the toxicity evaluation results. The results showed that AD disease models in BALB/c mice exhibited reduced ear epidermal thickness, scratching behavior, and mast cell infiltration. In conclusion, our results indicate that EAE has the potential to improve AD by upregulating the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway.


Assuntos
Dermatite Atópica , Erigeron , Humanos , Animais , Camundongos , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/tratamento farmacológico , Pele/metabolismo , Dinitroclorobenzeno/toxicidade , Erigeron/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Dinitrobenzenos/efeitos adversos , Dinitrobenzenos/metabolismo , Heme Oxigenase-1/metabolismo , Peróxido de Hidrogênio/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Camundongos Endogâmicos BALB C , Citocinas/metabolismo
10.
Molecules ; 29(3)2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38338436

RESUMO

Parkinson's disease (PD) is a progressive neurodegenerative disorder of the elderly for which there is no cure or disease-modifying therapy. Mitochondrial dysfunction and oxidative stress play a central role in dopaminergic neurodegeneration in PD. Therefore, antioxidants are considered a promising neuroprotective approach. In in vivo activity studies, 6-OHDA-induced oxidative stress in SH-SY5Y cells was established as a model of PD for cellular experiments. IIAVE (Ile-Ile-Ala-Val-Glu) was derived from Isochrysis zhanjiangensis octapeptide (IIAVEAGC), which has a small molecular weight. The structure and antioxidant activity of IIAVE were tested in a previous study and proved to have good antioxidant potential. In this study, the chemical properties of IIAVE were calculated using quantum chemical methods, including frontier molecular orbital (FMO), molecular electrostatic potential (MEP), natural population analysis (NPA), and global reactivity properties. The interaction of IIAVE with Bcl-2 and DJ-1 was investigated using the molecular docking method. The results showed that IIAVE promoted the activation of the Keap1/Nrf2 pathway and up-regulated the expression of the superoxide dismutase 1 (SOD-1) protein by inhibiting the level of reactive oxygen species (ROS) in cells. In addition, IIAVE inhibits ROS production and prevents 6-OHDA-induced oxidative damage by restoring mitochondrial membrane potential. Furthermore, IIAVE inhibited cell apoptosis by increasing the Bcl-2/Bax ratio and inhibiting the activation of Caspase-9 and Caspase-3. Thus, IIAVE may become a potential drug for the treatment and prevention of PD.


Assuntos
Haptófitas , Neuroblastoma , Fármacos Neuroprotetores , Doença de Parkinson , Humanos , Idoso , Neuroproteção , Espécies Reativas de Oxigênio/metabolismo , Oxidopamina/farmacologia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Haptófitas/metabolismo , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Linhagem Celular Tumoral , Apoptose , Antioxidantes/farmacologia , Doença de Parkinson/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
11.
J Neuroinflammation ; 21(1): 55, 2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38383481

RESUMO

BACKGROUND: Neuroinflammation substantially contributes to the pathology of Alzheimer's disease (AD), the most common form of dementia. Studies have reported that nuclear factor erythroid 2-related factor 2 (Nrf2) attenuates neuroinflammation in the mouse models of neurodegenerative diseases, however, the detailed mechanism remains unclear. METHODS: The effects of dimethyl fumarate (DMF), a clinically used drug to activate the Nrf2 pathway, on neuroinflammation were analyzed in primary astrocytes and AppNL-G-F (App-KI) mice. The cognitive function and behavior of DMF-administrated App-KI mice were evaluated. For the gene expression analysis, microglia and astrocytes were directly isolated from the mouse cerebral cortex by magnetic-activated cell sorting, followed by quantitative PCR. RESULTS: DMF treatment activated some Nrf2 target genes and inhibited the expression of proinflammatory markers in primary astrocytes. Moreover, chronic oral administration of DMF attenuated neuroinflammation, particularly in astrocytes, and reversed cognitive dysfunction presumably by activating the Nrf2-dependent pathway in App-KI mice. Furthermore, DMF administration inhibited the expression of STAT3/C3 and C3 receptor in astrocytes and microglia isolated from App-KI mice, respectively, suggesting that the astrocyte-microglia crosstalk is involved in neuroinflammation in mice with AD. CONCLUSION: The activation of astrocytic Nrf2 signaling confers neuroprotection in mice with AD by controlling neuroinflammation, particularly by regulating astrocytic C3-STAT3 signaling. Furthermore, our study has implications for the repositioning of DMF as a drug for AD treatment.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Camundongos , Animais , Doença de Alzheimer/complicações , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Fumarato de Dimetilo/farmacologia , Fumarato de Dimetilo/uso terapêutico , Camundongos Transgênicos , Doenças Neuroinflamatórias , Fator 2 Relacionado a NF-E2/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Modelos Animais de Doenças
12.
J Exp Clin Cancer Res ; 43(1): 52, 2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38383479

RESUMO

BACKGROUND: Osteosarcoma (OS) is one of most commonly diagnosed bone cancer. Circular RNAs (circRNAs) are a class of highly stable non-coding RNA, the majority of which have not been characterized functionally. The underlying function and molecular mechanisms of circRNAs in OS have not been fully demonstrated. METHOD: Microarray analysis was performed to identify circRNAs that are differentially-expressed between OS and corresponding normal tissues. The biological function of circKEAP1 was confirmed in vitro and in vivo. Mass spectrometry and western blot assays were used to identify the circKEAP1-encoded protein KEAP1-259aa. The molecular mechanism of circKEAP1 was investigated by RNA sequencing and RNA immunoprecipitation analyses. RESULTS: Here, we identified a tumor suppressor circKEAP1, originating from the back-splicing of exon2 of the KEAP1 gene. Clinically, circKEAP1 is downregulated in OS tumors and associated with better survival in cancer patients. N6-methyladenosine (m6A) at a specific adenosine leads to low expression of circKEAP1. Further analysis revealed that circKEAP1 contained a 777 nt long ORF and encoded a truncated protein KEAP1-259aa that reduces cell proliferation, invasion and tumorsphere formation of OS cells. Mechanistically, KEAP1-259aa bound to vimentin in the cytoplasm to promote vimentin proteasome degradation by interacting with the E3 ligase ARIH1. Moreover, circKEAP1 interacted with RIG-I to activate anti-tumor immunity via the IFN-γ pathway. CONCLUSION: Taken together, our findings characterize a tumor suppressor circKEAP1 as a key tumor suppressor regulating of OS cell stemness, proliferation and migration, providing potential therapeutic targets for treatment of OS.


Assuntos
Neoplasias Ósseas , MicroRNAs , Osteossarcoma , Humanos , MicroRNAs/genética , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , RNA Circular/genética , Vimentina/metabolismo , Linhagem Celular Tumoral , Fator 2 Relacionado a NF-E2/metabolismo , Osteossarcoma/patologia , Proteínas Supressoras de Tumor/metabolismo , Neoplasias Ósseas/patologia , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Movimento Celular/genética , Ubiquitina-Proteína Ligases/metabolismo
13.
Sci Rep ; 14(1): 4319, 2024 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-38383711

RESUMO

In the field of drug discovery, natural products have emerged as therapeutic agents for diseases such as cancer. However, their potential toxicity poses significant obstacles in the developing effective drug candidates. To overcome this limitation, we propose a pathway-screening method based on imaging analysis to evaluate cellular stress caused by natural products. We have established a cellular stress sensing system, named Hepa-ToxMOA, which utilizes HepG2 cells expressing green fluorescent protein (GFP) fluorescence under the control of transcription factor response elements (TREs) for transcription factors (AP1, P53, Nrf2, and NF-κB). Additionally, to augment the drug metabolic activity of the HepG2 cell line, we evaluated the cytotoxicity of 40 natural products with and without S9 fraction-based metabolic activity. Our finding revealed different activities of Hepa-ToxMOA depending on metabolic or non-metabolic activity, highlighting the involvement of specific cellular stress pathways. Our results suggest that developing a Hepa-ToxMOA system based on activity of drug metabolizing enzyme provides crucial insights into the molecular mechanisms initiating cellular stress during liver toxicity screening for natural products. The pathway-screening method addresses challenges related to the potential toxicity of natural products, advancing their translation into viable therapeutic agents.


Assuntos
Regulação da Expressão Gênica , NF-kappa B , Humanos , NF-kappa B/metabolismo , Células Hep G2 , Proteínas de Fluorescência Verde/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo
14.
Immun Inflamm Dis ; 12(2): e1193, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38372468

RESUMO

INTRODUCTION: The intestinal tract serves as an innate barrier, safeguarding the internal milieu from microorganisms and toxins. Various intestinal inflammatory diseases have a strong association with intestinal barrier dysfunction. The primary functional cells within the intestinal tract, intestinal epithelial cells (IECs) and their tight junctions (TJs), are crucial in preserving the integrity of this mechanical barrier. Resveratrol (Res), a plant-derived phenolic compound, exhibits a range of health-promoting benefits attributed to its anti-inflammatory properties. This study aims to examine Res's efficacy in bolstering IECs barrier function. METHODS: Dextran sulfate sodium (DSS) was employed to induce barrier dysfunction in IECs. Inflammatory cytokines in supernatants (interleukin [IL]-6, IL-1ß, tumor necrotic factor [TNF]-α, and IL-10) were quantified via enzyme-linked immunosorbent assay (ELISA). Then we assessed monolayer integrity using transepithelial electrical resistance (TEER). TJ protein expression (zonula occludens [ZO]-1 and Occludin) in IECs was evaluated through immunofluorescence and Western blot analysis. Network pharmacology helped identify the biological processes, signaling pathways, and key targets involved in Res's mitigation of DSS-induced IECs barrier dysfunction. The efficacy of the primary target was further corroborated using Western blot. RESULTS: Res was shown to increase cell viability and IL-10 expression while reducing TNF-α, IL-6, and IL-1ß levels, thus mitigating the inflammatory response. It enhanced TEER values and upregulated TJ protein expression (ZO-1 and Occludin). Network pharmacology revealed that Res potentially targets the NFE2L2 (nuclear factor erythroid-2-related factor 2, Nrf2), a vital antioxidant factor. Significantly, Res augmented Nrf2 and heme oxygenase 1 (HO-1) protein levels, counteracting oxidative stress in the IECs barrier dysfunction model. CONCLUSION: Overall, our findings suggested that Res ameliorated DSS-induced IECs barrier dysfunction by activating Nrf2/HO-1 pathway, showcasing significant therapeutic potential in the early stages of colitis.


Assuntos
Interleucina-10 , Mucosa Intestinal , Humanos , Células CACO-2 , Resveratrol/farmacologia , Resveratrol/metabolismo , Mucosa Intestinal/metabolismo , Interleucina-10/metabolismo , Sulfato de Dextrana/toxicidade , Sulfato de Dextrana/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Ocludina/metabolismo , Heme Oxigenase-1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
15.
Biol Sex Differ ; 15(1): 16, 2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38350966

RESUMO

BACKGROUND: Major depressive disorder (MDD) is a recurring affective disorder that is two times more prevalent in females than males. Evidence supports immune system dysfunction as a major contributing factor to MDD, notably in a sexually dimorphic manner. Nuclear factor erythroid 2-related factor 2 (Nrf2), a regulator of antioxidant signalling during inflammation, is dysregulated in many chronic inflammatory disorders; however, its role in depression and the associated sex differences have yet to be explored. Here, we investigated the sex-specific antidepressant and immunomodulatory effects of the potent Nrf2 activator dimethyl fumarate (DMF), as well as the associated gene expression profiles. METHODS: Male and female rats were treated with vehicle or DMF (25 mg/kg) whilst subjected to 8 weeks of chronic unpredictable stress. The effect of DMF treatment on stress-induced depression- and anxiety-like behaviours, as well as deficits in recognition and spatial learning and memory were then assessed. Sex differences in hippocampal (HIP) microglial activation and gene expression response were also evaluated. RESULTS: DMF treatment during stress exposure had antidepressant effects in male but not female rats, with no anxiolytic effects in either sex. Recognition learning and memory and spatial learning and memory were impaired in chronically stressed males and females, respectively, and DMF treatment rescued these deficits. DMF treatment also prevented stress-induced HIP microglial activation in males. Conversely, females displayed no HIP microglial activation associated with stress exposure. Last, chronic stress elicited sex-specific alterations in HIP gene expression, many of which were normalized in animals treated with DMF. Of note, most of the differentially expressed genes in males normalized by DMF were related to antioxidant, inflammatory or immune responses. CONCLUSIONS: Collectively, these findings support a greater role of immune processes in males than females in a rodent model of depression. This suggests that pharmacotherapies that target Nrf2 have the potential to be an effective sex-specific treatment for depression.


Major depressive disorder is two times more prevalent in females than males. Further, immune system dysfunction has been shown to contribute to the development of depression, with previous studies consistently reporting chronic low-grade inflammation in depressed individuals. Not surprisingly, the immune system dysfunction associated with depression appears to be sex specific. As such, whilst anti-inflammatory drugs have shown antidepressant effects in preclinical studies, the sex differences in these effects are seldomly investigated. Thus, this study sought to determine the sex-specific antidepressant and immune modulatory effects of dimethyl fumarate (DMF) treatment. DMF is a drug that activates the protein nuclear factor erythroid 2-related factor 2 to initiate anti-inflammatory processes. Here, male and female rats were exposed to 8 weeks of chronic stress whilst receiving daily DMF treatment. Subsequently, their expression of depression- and anxiety-like behaviours, as well as learning and memory deficits were assessed. Changes in the levels of an inflammatory marker in the brain and alterations in gene expression were also evaluated. DMF treatment had antidepressant effects in male rats only but did not have anti-anxiety effects in either sex. The learning and memory deficits in both sexes were rescued with DMF treatment. Notably, chronic stress increased inflammatory marker levels predominantly in male but not female rats, which was prevented by DMF treatment. In addition, DMF normalized several of the sex-specific gene alterations induced by chronic stress, with many of the male-specific genes relating to inflammatory processes. These data suggest that DMF may be an effective antidepressant treatment in males.


Assuntos
Depressão , Transtorno Depressivo Maior , Animais , Feminino , Masculino , Ratos , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Antioxidantes , Depressão/tratamento farmacológico , Depressão/metabolismo , Fumarato de Dimetilo/farmacologia , Fumarato de Dimetilo/uso terapêutico , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo
16.
J Biochem Mol Toxicol ; 38(3): e23661, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38369721

RESUMO

Phenothiazines (PTZs) are an emerging group of molecules showing effectiveness toward redox signaling and reduction of oxidative injury to cells, via the activation on Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 (Nrf2). Although several electrophilic and indirect Nrf2 activators have been reported, the risk of "off-target" effect due to the complexity of their molecular mechanisms of action, has aroused research interest toward non-electrophilic and direct modulators of Nrf2 pathway, such as PTZs. This review represents the first overview on the roles of PTZs as non-electrophilic Nrf2 activator and free radical scavengers, as well as on their potential therapeutic effects in oxidative stress-mediated diseases. Here, we provide a collective and comprehensive information on the PTZs ability to scavenge free radicals and activate the Nrf2 signaling pathway, with the aim to broaden the knowledge of their therapeutic potentials and to stimulate innovative research ideas.


Assuntos
Antioxidantes , Fator 2 Relacionado a NF-E2 , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Sequestradores de Radicais Livres , Transdução de Sinais , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo
17.
Int J Nanomedicine ; 19: 1431-1450, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38371455

RESUMO

Introduction: Basic fibroblast growth factor (bFGF) shows great potential for preventing vascular dementia (VD). However, the blood‒brain barrier (BBB) and low bioavailability of bFGF in vivo limit its application. The present study investigated how nasal administration of bFGF-loaded nanoliposomes (bFGF-lips) affects the impaired learning and cognitive function of VD mice and the underlying mechanism involved. Methods: A mouse model of VD was established through repeated cerebral ischemia‒reperfusion. A Morris water maze (MWM) and novel object recognition (NOR) tests were performed to assess the learning and cognitive function of the mice. Hematoxylin and eosin (HE) staining, Nissl staining and TUNEL staining were used to evaluate histopathological changes in mice in each group. ELISA and Western blot analysis were used to investigate the molecular mechanism by which bFGF-lips improve VD incidence. Results: Behavioral and histopathological analyses showed that cognitive function was significantly improved in the bFGF-lips group compared to the VD and bFGF groups; in addition, abnormalities and the apoptosis indices of hippocampal neurons were significantly decreased. ELISA and Western blot analysis revealed that bFGF-lips nasal administration significantly increased the concentrations of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), bFGF, B-cell lymphoma 2 (Bcl-2), phosphorylated protein kinase B (PAKT), nuclear factor erythroid 2-related factor 2 (Nrf2), NAD(P)H quinone oxidoreductase 1 (NQO1) and haem oxygenase-1 (HO-1) in the hippocampus of bFGF-lips mice compared with the VD and bFGF groups. Furthermore, the concentrations of malondialdehyde (MDA), caspase-3 and B-cell lymphoma 2-associated X (Bax) were clearly lower in the bFGF-lips group than in the VD and bFGF groups. Conclusion: This study confirmed that the nasal administration of bFGF-lips significantly increased bFGF concentrations in the hippocampi of VD mice. bFGF-lips treatment reduced repeated I/R-induced neuronal apoptosis by regulating apoptosis-related protein concentrations and activating the phosphatidylinositol-3-kinase (PI3K)/(AKT)/Nrf2 signaling pathway to inhibit oxidative stress.


Assuntos
Isquemia Encefálica , Demência Vascular , Camundongos , Animais , Demência Vascular/tratamento farmacológico , Demência Vascular/metabolismo , Demência Vascular/patologia , Fator 2 de Crescimento de Fibroblastos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Administração Intranasal , Estresse Oxidativo , Infarto Cerebral , Isquemia Encefálica/tratamento farmacológico , Cognição , Reperfusão , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Apoptose
18.
Chin J Nat Med ; 22(2): 137-145, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38342566

RESUMO

Excessive oxidative stress impairs cartilage matrix metabolism balance, significantly contributing to osteoarthritis (OA) development. Celastrol (CSL), a drug derived from Tripterygium wilfordii, has recognized applications in the treatment of cancer and immune system disorders, yet its antioxidative stress mechanisms in OA remain underexplored. This study aimed to substantiate CSL's chondroprotective effects and unravel its underlying mechanisms. We investigated CSL's impact on chondrocytes under both normal and inflammatory conditions. In vitro, CSL mitigated interleukin (IL)-1ß-induced activation of proteinases and promoted cartilage extracellular matrix (ECM) synthesis. In vivo, intra-articular injection of CSL ameliorated cartilage degeneration and mitigated subchondral bone lesions in OA mice. Mechanistically, it was found that inhibiting nuclear factor erythroid 2-related factor 2 (NRF2) abrogated CSL-mediated antioxidative functions and exacerbated the progression of OA. This study is the first to elucidate the role of CSL in the treatment of OA through the activation of NRF2, offering a novel therapeutic avenue for arthritis therapy.


Assuntos
Fator 2 Relacionado a NF-E2 , Osteoartrite , Camundongos , Animais , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Osteoartrite/patologia , Triterpenos Pentacíclicos/farmacologia , Triterpenos Pentacíclicos/metabolismo , Condrócitos , Interleucina-1beta
19.
Sci Rep ; 14(1): 3469, 2024 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-38342928

RESUMO

The aim of this study was to investigate the potential of Ipomoea carnea flower methanolic extract (ICME) as a natural gastroprotective therapy against ethanol-induced gastric ulcers, particularly in individuals exposed to ionizing radiation (IR). The study focused on the Nrf2/HO-1 signaling pathway, which plays a crucial role in protecting the gastrointestinal mucosa from oxidative stress and inflammation. Male Wistar rats were divided into nine groups, the control group received distilled water orally for one week, while other groups were treated with ethanol to induce stomach ulcers, IR exposure, omeprazole, and different doses of ICME in combination with ethanol and/or IR. The study conducted comprehensive analyses, including LC-HRESI-MS/MS, to characterize the phenolic contents of ICME. Additionally, the Nrf2/HO-1 pathway, oxidative stress parameters, gastric pH, and histopathological changes were examined. The results showed that rats treated with IR and/or ethanol exhibited histopathological alterations, increased lipid peroxidation, decreased antioxidant enzyme activity, and reduced expression levels of Nrf2 and HO-1. However, pretreatment with ICME significantly improved these parameters. Phytochemical analysis identified 39 compounds in ICME, with flavonoids, hydroxybenzoic acids, and fatty acids as the predominant compounds. Virtual screening and molecular dynamics simulations suggested that ICME may protect against gastric ulceration by inhibiting oxidative stress and inflammatory mediators. In conclusion, this study demonstrates the potential of ICME as a natural gastroprotective therapy for preventing gastric ulcers. These findings contribute to the development of novel interventions for gastrointestinal disorders using natural plant extracts particularly in individuals with a history of radiation exposure.


Assuntos
Extratos Vegetais , Úlcera Gástrica , Animais , Ratos , Antioxidantes/farmacologia , Etanol/química , Mucosa Gástrica/metabolismo , Metanol/química , Fator 2 Relacionado a NF-E2/metabolismo , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Ratos Wistar , Úlcera Gástrica/tratamento farmacológico , Úlcera Gástrica/etiologia , Úlcera Gástrica/prevenção & controle , Espectrometria de Massas em Tandem , Úlcera/patologia
20.
Immun Inflamm Dis ; 12(2): e1185, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38353312

RESUMO

BACKGROUND: Pneumonia is the leading cause of death among children under five, and kill almost two million children each year. Quercetin, a flavonoid polyphenolic compound, exerts many beneficial biological activities, including anti-inflammatory functions. Our study aimed to investigate the possibility of quercetin as a therapeutic agent for pneumonia and its role in the inflammatory response induced by lipopolysaccharide (LPS). METHODS: LPS induced human alveolar epithelial cell A549 as a lung inflammation model in vitro. The effects of quercetin on the production of cytokines and the expression of related-proteins were detected by Enzyme-Linked ImmunoSorbent Assay and Western Blot, respectively. Cell Counting Kit-8 assay was used to detect cell viability. flow cytometry was used to measure cell apoptosis. NO levels were also analyzed through NO kit. RESULTS: Our results found that quercetin attenuated the release of IL-1ß, IL-6, PGE2, and nitrite in LPS-induced A549 cells. In addition, quercetin inhibits cell apoptosis and relieves ROS generation in LPS-induced A549 cells. Quercetin also inhibits LPS-induced NF-κB activation. They have upregulated the expression of nuclear factor erythroid 2 (Nrf2) and HO-1. CONCLUSION: In conclusion, these results suggested that quercetin attenuates LPS-induced inflammation in A549 by activating the Nrf2 signaling pathway.


Assuntos
Lipopolissacarídeos , Pneumonia , Criança , Humanos , Lipopolissacarídeos/toxicidade , Quercetina/farmacologia , Quercetina/uso terapêutico , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Células Epiteliais/metabolismo , Pulmão
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