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1.
Oxid Med Cell Longev ; 2022: 5628946, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35910837

RESUMO

Age-related cataract (ARC) is the common cause of blindness globally. Reactive oxygen species (ROS), one of the greatest contributors to aging process, leads to oxidative damage and senescence of lens epithelial cells (LECs), which are involved in the pathogenesis of ARC. Biliverdin reductase A (BVRA) has ROS-scavenging ability by converting biliverdin (BV) into bilirubin (BR). However, little is known about the protective effect of BVRA against ARC. In the present study, we measured the expression level of BVRA and BR generation in human samples. Then, the antioxidative property of BVRA was compared between the young and senescent LECs upon stress condition. In addition, we evaluated the effect of BVRA on attenuating H2O2-induced premature senescence in LECs. The results showed that the mRNA expression level of BVRA and BR concentration were decreased in both LECs and lens cortex of age-related nuclear cataract. Using the RNA interference technique, we found that BVRA defends LECs against oxidative stress via (i) restoring mitochondrial dysfunction in a BR-dependent manner, (ii) inducing heme oxygenase-1 (HO-1) expression directly, and (iii) promoting phosphorylation of ERK1/2 and nuclear delivery of nuclear factor erythroid 2-related factor 2 (Nrf2). Intriguingly, the antioxidative effect of BVRA was diminished along with the reduced BR concentration and repressed nuclear translocation of BVRA and Nrf2 in senescent LECs, which would be resulted from the decreased BVRA activity and impaired nucleocytoplasmic trafficking. Eventually, we confirmed that BVRA accelerates the G1 phase transition and prevents against H2O2-induced premature senescence in LECs. In summary, BVRA protects LECs against oxidative stress and cellular senescence in ARC by converting BV into BR, inducing HO-1 expression, and activating the ERK/Nrf2 pathway. This trial is registered with ChiCTR2000036059.


Assuntos
Catarata , Fator 2 Relacionado a NF-E2 , Antioxidantes/farmacologia , Bilirrubina/metabolismo , Catarata/patologia , Senescência Celular , Células Epiteliais/metabolismo , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Peróxido de Hidrogênio/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Oxirredutases atuantes sobre Doadores de Grupo CH-CH , Espécies Reativas de Oxigênio/metabolismo
2.
Eur Rev Med Pharmacol Sci ; 26(13): 4574-4582, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35856346

RESUMO

OBJECTIVE: To investigate the effect of dexmedetomidine on the apoptosis of cerebral nerve cells after cerebral hemorrhage (CH) in rats and its molecular mechanism. MATERIALS AND METHODS: The rat model of CH was established by autologous blood injection. A total of 60 specific pathogen-free (SPF)-grade rats were randomly divided into sham-operation group, model group and dexmedetomidine group, and each group involved 20 rats. Rat brain water content was compared among the three groups. Besides, rat neurological function of the three groups was evaluated at 3, 5 and 7 d after operation by neurological function scoring. Western blotting assay was adopted to detect protein levels of apoptosis-related genes [B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax)] in rat brain tissues in the three groups. Moreover, the apoptosis level in the brain tissues in the groups was measured through terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Biochemical tests were conducted to determine activities of reduced glutathione (GSH), superoxide dismutase (SOD) and malondialdehyde (MDA) in the brain tissues among the three groups. Furthermore, the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1)/NAD(P)H quinone oxidoreductase 1 (NQO1) signaling pathway in the brain tissues of the three groups of rats was examined via Western blotting assay. An in vitro oxygen-glucose deprivation (OGD) model was prepared using SH-SY5Y cells. In addition, Nrf2 was intervened in SH-SY5Y cells by small hairpin ribonucleic acid (shRNA) transfection. Finally, flow cytometry and Annexin V/PI assay were performed to detect the response of cells to dexmedetomidine in OGD + dexmedetomidine + sh-Nrf2 group. RESULTS: The brain water content and the neurological function score at 3, 5 and 7 d after operation were remarkably reduced in dexmedetomidine group compared with those in model group. The results of Western blotting and TUNEL assays indicated that dexmedetomidine group had a notably lowered apoptosis level in the brain tissues. Additionally, the biochemical test results manifested that activities of GSH and SOD were enhanced and that of MDA decreased in the brain tissues of dexmedetomidine group. Protein levels of Nrf2, HO-1 and NQO1 in the brain tissues were distinctly higher in dexmedetomidine group than those in model group. According to the results of flow cytometry, the apoptosis rate in OGD + dexmedetomidine + sh-Nrf2 group rose prominently compared with that in OGD + dexmedetomidine group. CONCLUSIONS: Dexmedetomidine inhibits the nerve cell apoptosis in rat brain tissues by activating the Nrf2/HO-1/NQO1 signaling pathway in rat CH models.


Assuntos
Dexmedetomidina , Neuroblastoma , Animais , Apoptose , Hemorragia Cerebral/tratamento farmacológico , Dexmedetomidina/farmacologia , Heme Oxigenase-1/metabolismo , Humanos , NAD(P)H Desidrogenase (Quinona)/genética , Fator 2 Relacionado a NF-E2/metabolismo , Neurônios/metabolismo , Estresse Oxidativo , Ratos , Transdução de Sinais , Superóxido Dismutase/metabolismo , Água
3.
Front Immunol ; 13: 887000, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35860274

RESUMO

Ischemic stroke is caused by a sudden reduction in cerebral blood flow that subsequently induces a complex cascade of pathophysiological responses, leading to brain inflammation and irreversible infarction. 4-ethylguaiacol (4-EG) is reported to suppress inflammatory immune responses. However, whether 4-EG exerts anti-inflammatory effects in ischemic stroke remains unexplored. We evaluated the therapeutic potential of 4-EG and examined the cellular and molecular mechanisms underlying the protective effects of 4-EG in ischemic stroke. The effect of 4-EG in ischemic stroke was determined by using a transient middle cerebral artery occlusion (MCAO) animal model followed by exploring the infarct size, neurological deficits, microglia activation, inflammatory cytokine production, blood-brain barrier (BBB) disruption, brain endothelial cell adhesion molecule expression, and microglial heme oxygenase-1 (HO-1) expression. Nrf2-/- and HO-1 inhibitor ZnPP-treated mice were also subjected to MCAO to evaluate the role of the Nrf2/HO-1 pathway in 4-EG-mediated protection in ischemic stroke. We found that 4-EG attenuated infarct size and neurological deficits, and lessened BBB disruption in ischemic stroke. Further investigation revealed that 4-EG suppressed microglial activation, peripheral inflammatory immune cell infiltration, and brain endothelial cell adhesion molecule upregulation in the ischemic brain. Finally, we identified that the protective effect of 4-EG in ischemic stroke was abolished in Nrf2-/- and ZnPP-treated MCAO mice. Our results identified that 4-EG confers protection against ischemic stroke and reveal that the protective effect of 4-EG in ischemic stroke is mediated through the induction of the Nrf2/HO1 pathway. Thus, our findings suggest that 4-EG could be developed as a novel therapeutic agent for the treatment of ischemic stroke.


Assuntos
Lesões Encefálicas , AVC Isquêmico , Fármacos Neuroprotetores , Animais , Moléculas de Adesão Celular , Guaiacol/análogos & derivados , Heme Oxigenase-1/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológico , AVC Isquêmico/tratamento farmacológico , Camundongos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Doenças Neuroinflamatórias , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico
4.
Front Immunol ; 13: 864638, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35837403

RESUMO

Neutrophil extracellular traps (NETs) immobilize pathogens during early stages of systemic inflammation but as the reaction progresses they become detrimental to endothelial cells and the organ-specific cells. For this reason it would be of importance to control their formation by either physiological or pharmacological means. Endogenously, formation of NETs is under control of cellular and whole organism metabolism as shown previously in the course of bacterial systemic inflammation, obesity or the combination of the two. Numerous leukocytes are subjected to immunometabolic regulation and in macrophages exposure to lipopolysaccharide (LPS) leads to two breaks in the Krebs cycle that impact this cell functioning. As a consequence of the first break, anti-microbial itaconic acid (itaconate) is produced whereas the second break activates hypoxia-inducible factor-1α (Hif-1α). In turn, itaconate activates transcription of the anti-inflammatory nuclear factor erythroid 2-related factor 2 (Nrf2) which upregulates cyto-protective heme oxygenase (HO-1). Here we report that exogenously added derivative of the itaconic acid, 4-octyl itaconate (4-OI), diminishes formation of NETs by neutrophils of either normal (lean) or obese mice, and independently of the age of the animals or immunoaging. Elucidating the mechanism of this inhibition we unravel that although Nrf2/HO-1 expression itself is not altered by 4-OI, it is up-regulated when compared against the NET formation while Hif-1α is downregulated in 4-OI-pre-treated LPS-stimulated neutrophils in either way. We further show that blockage of Hif-1α by its specific inhibitor diminishes NET release as does inhibition by 4-OI. Also inhibition of HO-1 activity correlates with diminished LPS-induced NET release upon pre-treatment with 4-OI albeit LPS alone induced NETs are not HO-1-dependent. In summary, we unravel that 4-OI inhibits NET formation by murine neutrophils independently of their origin (health vs. metabolically challenged animals) and the age of individuals/immunosenescence via inhibition of Hif-1α and induction of HO-1.


Assuntos
Armadilhas Extracelulares , Heme Oxigenase (Desciclizante) , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Animais , Células Endoteliais/metabolismo , Armadilhas Extracelulares/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Heme Oxigenase-1/metabolismo , Hipóxia , Inflamação , Lipopolissacarídeos/farmacologia , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Succinatos
5.
Acta Neurobiol Exp (Wars) ; 82(2): 197-206, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35833819

RESUMO

Pachymic acid (PA) plays a neuroprotective role during cerebral ischemia/reperfusion. However, the protective mechanisms of PA in cerebral ischemia/reperfusion have been not fully determined. This investigation aims to explore the neuroprotective role of PA in ischemia/reperfusion via miR­155/NRF2/HO­1 axis. The N2a cell line was induced by hypoxia/reoxygenation (H/R) to simulate the neuronal damage that occurs during cerebral ischemia/reperfusion. PA was used to treat H/R­induced N2a cells. An MTT assay was used to determine cell viability. The protein levels of Bcl­2, Bax, heme oxygenase­1 (HO­1) and nuclear factor E2­related factor 2 (NRF2) were measured via Western blot analysis. The level of apoptosis of N2a cells was determined by flow cytometry. The expression levels of miR­155 and NRF2 were quantified by real­time PCR. PA treatment inhibits the increase in apoptosis induced by H/R and also enhances the viability of cells exposed to H/R. PA reverses the increased expression of miR­155 caused by H/R. Furthermore, H/R does not change the expression of HO­1 and NRF2, but PA upregulates the expressions of HO­1 and NRF2. Additionally, NRF2 is the target of miR­155. Inhibiting miR­155 contributes to increased cell viability and decreased apoptosis via targeting the NRF2/HO­1 pathway. Overall, PA prevents neuronal cell damage induced by hypoxia/reoxygenation via miR­155/NRF2/HO­1 axis.


Assuntos
Isquemia Encefálica , MicroRNAs , Apoptose , Heme Oxigenase-1/metabolismo , Humanos , Hipóxia , MicroRNAs/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Transdução de Sinais/fisiologia , Triterpenos
6.
Pharmacol Rep ; 74(4): 557-569, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35882765

RESUMO

Movement disorders are neurological conditions characterized by involuntary motor movements, such as dystonia, ataxia, chorea myoclonus, tremors, Huntington's disease (HD), and Parkinson's disease (PD). It is classified into two categories: hypokinetic and hyperkinetic movements. Globally, movement disorders are a major cause of death. The pathophysiological process is initiated by excessive ROS generation, mitochondrial dysfunction, neuroinflammation, and neurotransmitters imbalance that lead to motor dysfunction in PD and HD patients. Several endogenous targets including Nrf2 maintain oxidative balance in the body. Activation of Nrf2 signaling is regulated by the enzyme glycogen synthase kinase (GSK-3ß). In the cytoplasm, inhibition of GSK-3ß regulates cellular proliferation, homeostasis, and apoptotic process by stimulating the nuclear factor erythroid 2 (Nrf2) pathway which is involved in the elevation of the cellular antioxidant enzymes which controls the ROS generation. The activation of Nrf2 increases the expression of antioxidant response elements (ARE), such as (Hemeoxygenase-1) HO-1, which decreases excessive cellular stress, mitochondrial dysfunction, apoptosis, and neuronal degeneration, which is the major cause of motor dysfunction. The present review explores the GSK-3ß-mediated neuroprotection in various movement disorders through the Nrf2/HO-1 antioxidant pathway. This review provides a link between GSK-3ß and the Nrf2/HO-1 signaling pathway in the treatment of PD and HD. In addition to that it highlights various GSK-3ß inhibitors and the Nrf2/HO-1 activators, which exert robust neuroprotection against motor disorders. Therefore, the present review will help in the discovery of new therapy for PD and HD patients.


Assuntos
Transtornos dos Movimentos , Fator 2 Relacionado a NF-E2 , Antioxidantes/farmacologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Heme Oxigenase-1/metabolismo , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio , Transdução de Sinais
7.
Cardiovasc Ther ; 2022: 7576388, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35812724

RESUMO

Purpose: An arteriovenous fistula (AVF) is the preferred vascular access mode for maintenance hemodialysis, and access stenosis and thrombosis are the primary causes of AVF dysfunction. This study is aimed at exploring the molecular mechanisms underlying AVF development and the roles of the heme oxygenase 1/peroxisome proliferator-activated receptor gamma (HO-1/PPAR-γ) pathway in AVF. Method: AVF model mice were established, and the vascular tissues from the arteriovenous anastomosis site were sent for mRNA sequencing. Differentially expressed mRNAs (DEmRNAs) were screened and subjected to functional analysis. Thereafter, the mice with HO-1 knockdown and coprotoporphyrin IX chloride (COPP) pretreatment were used to investigate the roles of the HO-1/PPAR-γ pathway in AVF. Results: By sequencing, 2514 DEmRNAs, including 1323 upregulated and 1191 downregulated genes, were identified. These DEmRNAs were significantly enriched in the PPAR signaling pathway, AMPK signaling pathway, glucagon signaling pathway, IL-17 signaling pathway, and Toll-like receptor signaling pathway. High expression of HO-1 and PPAR-γ reduced endothelial damage and intimal hyperplasia during AVF maturation. After AVF was established, the levels of transforming growth factor-ß (TGF-ß), interleukin-1ß (IL-1ß), interleukin-18 (IL-18), and reactive oxygen species (ROS) were significantly increased (P < 0.05), and HO-1 normal expression and COPP pretreatment evidently decreased their levels in AVF (P < 0.05). Additionally, AVF significantly upregulated HO-1 and PPAR-γ and downregulated MMP9, and COPP pretreatment and HO-1 normal expression further upregulated and downregulated their expression. Conclusion: The HO-1/PPAR-γ pathway may suppress intimal hyperplasia induced by AVF and protect the intima of blood vessels by regulating MMP9 and ROS, thus mitigating AVF dysfunction.


Assuntos
Fístula Arteriovenosa , Heme Oxigenase-1 , Proteínas de Membrana , PPAR gama , Túnica Íntima , Animais , Fístula Arteriovenosa/metabolismo , Heme Oxigenase-1/metabolismo , Hiperplasia , Metaloproteinase 9 da Matriz/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Estresse Oxidativo , PPAR gama/metabolismo , RNA Mensageiro/análise , Espécies Reativas de Oxigênio , Diálise Renal
8.
Neuroreport ; 33(11): 451-462, 2022 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-35775321

RESUMO

The secondary injury plays a vital role in the development of spinal cord injury (SCI), which is characterized by the occurrence of oxidative stress, neuronal apoptosis, and inflammatory response. Notoginsenoside R1 (NGR1) has been involved in the modulation of antioxidative stress and anti-inflammatory response. However, its roles in SCI-induced injury are still unknown. We explored the therapeutic effect of NGR1 and its underlying mechanism after SCI by using behavioral, biochemical, and immunohistochemical techniques. The administration of NGR1 after SCI enhanced the neurological function, and mitigated tissue damage and motor neuron loss than those in SCI + vehicle group. Meanwhile, significantly increased expression of Nrf2 protein and HO-1 protein was found in the SCI + NGR1 group compared with those in the SCI + vehicle group. In addition, the inhibitory effects of oxidative stress, apoptotic neuron ratio, and neuronal inflammation in the SCI + NGR1 group can be partially reversed when the Nrf2/HO-1 signaling pathway was inhibited by ML385. Our results indicate that the administration of NGR1 can attenuate oxidative stress, neuronal apoptosis, and inflammation by activating the Nrf2/HO-1 signaling pathway after SCI, thereby improving neurological function.


Assuntos
Ginsenosídeos , Heme Oxigenase-1 , Traumatismos da Medula Espinal , Apoptose/efeitos dos fármacos , Ginsenosídeos/farmacologia , Heme Oxigenase-1/metabolismo , Humanos , Inflamação/tratamento farmacológico , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/metabolismo
9.
Int J Mol Sci ; 23(13)2022 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-35806040

RESUMO

Heme oxygenase (HO) has both beneficial and detrimental effects via its metabolites, including carbon monoxide (CO), biliverdin or bilirubin, and ferrous iron. HO-1 is an inducible form of HO that is upregulated by oxidative stress, nitric oxide, CO, and hypoxia, whereas HO-2 is a constitutive form that regulates vascular tone and homeostasis. In brains injured by trauma, ischemia-reperfusion, or Alzheimer's disease (AD), the long-term expression of HO-1 can be detected, which can lead to cytotoxic ferroptosis via iron accumulation. In contrast, the transient induction of HO-1 in the peri-injured region may have regenerative potential (e.g., angiogenesis, neurogenesis, and mitochondrial biogenesis) and neurovascular protective effects through the CO-mediated signaling pathway, the antioxidant properties of bilirubin, and the iron-mediated ferritin synthesis. In this review, we discuss the dual roles of HO-1 and its metabolites in various neurovascular diseases, including age-related macular degeneration, ischemia-reperfusion injury, traumatic brain injury, Gilbert's syndrome, and AD.


Assuntos
Heme Oxigenase (Desciclizante) , Heme Oxigenase-1 , Bilirrubina/metabolismo , Biliverdina/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Ferro/metabolismo
10.
Int J Mol Sci ; 23(13)2022 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-35806120

RESUMO

Deoxyshikonin (DSK), a phytochemical constituent, has been documented to elicit various oncostatic properties alone or in combination with established therapeutics. However, its role in restraining oral squamous cell carcinoma (OSCC) is mostly unclear. Here, we examined the tumor-suppressive effect of DSK and explored the molecular mechanisms underlying DSK's activities on controlling oral cancer. Our results showed that DSK dose-dependently lessened the cell viability of tongue cancer cell lines, involving induction of cell cycle arrest at the sub-G1 phase and apoptotic cell death. Moreover, a unique signature of apoptosis-related proteins, including augmented nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) expression and caspase activation, was observed in DSK-treated tongue cancer cell lines. Furthermore, DSK-mediated upregulation of HO-1 and cleavage of caspase-9 and -3 were significantly inhibited by pharmacological blockage of p38 kinase. Collectively, these data revealed that DSK halted cell cycle progression and elicited cell apoptosis in tongue cancer cell lines, reshaping a p38-dependent profile of apoptotic proteome. Our findings provided novel insights into the therapeutic implications of a natural compound on the management of OSCC.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Bucais , Neoplasias da Língua , Apoptose , Proteínas Reguladoras de Apoptose/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Heme Oxigenase-1/metabolismo , Humanos , Neoplasias Bucais/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Naftoquinonas , Neoplasias da Língua/tratamento farmacológico , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
11.
Int J Mol Sci ; 23(14)2022 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-35887117

RESUMO

The objective of this study was to investigate the protective effects and potential molecular mechanisms of procyanidin B2 (PB2) in MAC-T (mammary alveolar cells-large T antigen) cells during heat stress (HS). The MAC-T cells were divided into three treatment groups: control (37 °C), HS (42 °C), and PB2 + HS (42 °C). Compared with MAC-T cells that were consistently cultured at 37 °C, acute HS treatment remarkably decreased cell viability, reduced activities of catalase (CAT), superoxide dismutase (SOD), and total antioxidant capacity (T-AOC), and elevated intracellular levels of malondialdehyde (MDA) and reactive oxygen species (ROS). Additionally, nuclear factor erythroid 2-related factor 2 (Nrf2) was activated and translocated to the nucleus, in accompaniment with upregulation of Nrf2, heme oxygenase 1 (HO-1), thioredoxin reductase 1 (Txnrd1), and heat shock protein 70 (HSP70). In parallel, both mRNA transcript and actual protein secretion of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß), were increased by heat stress. Pretreatment of MAC-T cells with 0~25 µM PB2 alleviated the decline of cell viability by HS in a dose-dependent fashion and protected cells against HS-induced oxidative stress, as evidenced by significantly improved CAT, SOD, and T-AOC activity, as well as with decreased MDA and ROS generation. Furthermore, PB2 further activated the Nrf2 signaling pathway and reversed the inflammatory response induced by HS. Silencing of Nrf2 by si-Nrf2 transfection not only exacerbated HS-induced cell death and provoked oxidative stress and the inflammatory response, but also greatly abolished the cytoprotective effects under HS of PB2. In summary, PB2 protected MAC-T cells against HS-induced cell death, oxidative stress, and inflammatory response, partially by operating at the Nrf2 signal pathway.


Assuntos
Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Biflavonoides , Catequina , Bovinos , Células Epiteliais/metabolismo , Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Proantocianidinas , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo
12.
Neurosci Lett ; 784: 136754, 2022 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-35753614

RESUMO

In addition to significant antioxidant properties, melatonin exhibits neuroprotective effects against various neurological diseases including traumatic brain injury (TBI) and ischemic stroke. Several potential mechanisms have been reported in the neuroprotection of melatonin among patients with TBI. Notably, the heme oxygenase-1 (HO-1)/cAMP response element-binding protein (CREB) signaling pathway is implicated in the development of a depressive state. Moreover, the activity of CREB in the nucleus accumbens (NAc) participates in reward and motivation, further contributing to depression induced by TBI. This study aims to explore whether melatonin could mitigate TBI-induced depression by activating of HO-1/CREB signal in a rodent model of weight-drop. As a consequence, melatonin (10 mg/kg) attenuated TBI-induced elevated immobility time in the force swim test, decreased time spent sniffing the novel rat in 3-chambered social test, and downregulated phosphorylated CERB in the NAc. However, a special inhibitor of HO-1 (SnPP) via intracerebroventricular injection partially reversed the neuroprotective effects of melatonin. Furthermore, melatonin decreased the number of summarized intersects in the astrocyte, A1-type astrocytes, IL-6-positive astrocytes in the NAc after TBI exposure, nevertheless, these changes could partially be restored by SnPP. Therefore, our findings demonstrate a novel neuroprotective mechanism for melatonin against TBI which can be a potential neuroprotective agent for the treatment of TBI-induced depression.


Assuntos
Lesões Encefálicas Traumáticas , Melatonina , Fármacos Neuroprotetores , Animais , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Depressão/tratamento farmacológico , Depressão/etiologia , Heme Oxigenase-1/metabolismo , Melatonina/farmacologia , Melatonina/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Ratos
13.
J Ethnopharmacol ; 296: 115497, 2022 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-35738472

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Rhaponticum uniflorum (L.) DC is a member of the Compositae family. Loulu flowers (LLF) is the inflorescence of this plant, which is a commonly used Mongolian medicine for the treatment of inflammatory diseases due to its heat-clearing and detoxifying properties. It is used caused by. However, its anti-inflammatory mechanisms are not clear. AIM OF THIS STUDY: We investigated whether ethanol extracts of LLF can alleviate LPS-induced acute lung injury and explored the mechanism involved. MATERIAL AND METHODS: BALB/C mice were intragastrically administered with sodium carboxymethyl cellulose (0.5%, 1 mL/100 g) or ethanol extracts of LLF at a dose of 100, 200, and 400 mg/kg, once daily, for 3 days. Subsequently, mice models of acute lung injury were established by LPS and used for the determination of anti-inflammatory effects of LLF. After 6 h of treatment, mice were sacrificed to collect lung tissues and bronchoalveolar lavage fluid (BALF). H&E staining assay was performed on the tissues for pathological analysis. The ELISA test was conducted to measure NO, IL-6, TNF-α, MPO, SOD, CAT, MDA and GSH-PX levels. The expression level of proteins associated with the Nrf2/HO-1 and MAPK/NF-κB signaling pathways were determined using Western blot analysis. Levels of F4/80 and Nrf2 in lungs were quantified using immunohistochemistry. RESULTS: Oral administration of LLF extracts alleviated LPS-induced pathological alterations, reduced lung W/D weight ratio, decreased levels of TP, pro-inflammatory factors (TNF-α and IL-6), and NO in BALF. Pretreatment with LLF extract downregulated F4/80 expression in lung tissue and suppressed LPS-induced elevations in BALF and lung tissue levels of MPO. Moreover, treatment with LLF extract reduced the expression level of proteins associated with the MAPK signaling pathway (p-p38, p-JNK, p-ERK) and TLR4/NF-κB signaling pathways (TLR4, Myd88, p-IκB, p-p65). Moreover, LLF extract upregulated Nrf2, HO-1 and NQO1 protein levels, downregulated Keap1 protein level. Immunohistochemical analysis revealed that LLF reduced the LPS-induced increase in Nfr2 expression in lung tissues. CONCLUSION: Ethanol extracts of LLF ameliorated LPS-induced acute lung injury by suppressing inflammatory response and enhancing antioxidation capacity, which correlated with the MAPK/NF-κB and Nfr2/HO-1 signaling pathways.


Assuntos
Lesão Pulmonar Aguda , Asteraceae , Leuzea , Extratos Vegetais , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Animais , Anti-Inflamatórios , Asteraceae/química , Etanol , Heme Oxigenase-1/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflorescência , Interleucina-6/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Leuzea/química , Lipopolissacarídeos/toxicidade , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
15.
Free Radic Biol Med ; 188: 134-145, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35691510

RESUMO

Sepsis is a complex disease due to dysregulated host response to infection. Oxidative stress and mitochondrial dysfunction leading to metabolic dysregulation are among the hallmarks of sepsis. The transcription factor NRF2 (Nuclear Factor E2-related factor2) is a master regulator of the oxidative stress response, and the NRF2 mediated antioxidant response is negatively regulated by BTB and CNC homology 1 (BACH1) protein. This study tested whether Bach1 deletion improves organ function and survival following polymicrobial sepsis induced by cecal ligation and puncture (CLP). We observed enhanced post-CLP survival in Bach1-/- mice with a concomitantly increased liver HO-1 expression, reduced liver injury and oxidative stress, and attenuated systemic and tissue inflammation. After sepsis induction, the liver mitochondrial function was better preserved in Bach1-/- mice. Furthermore, BACH1 deficiency improved liver and lung blood flow in septic mice, as measured by SPECT/CT. RNA-seq analysis identified 44 genes significantly altered in Bach1-/- mice after sepsis, including HMOX1 and several genes in lipid metabolism. Inhibiting HO-1 activity by Zinc Protoporphyrin-9 worsened organ function in Bach1-/- mice following sepsis. We demonstrate that mitochondrial bioenergetics, organ function, and survival following experimental sepsis were improved in Bach1-/- mice through the HO-1-dependent mechanism and conclude that BACH1 is a therapeutic target in sepsis.


Assuntos
Heme Oxigenase-1/metabolismo , Proteínas de Membrana/metabolismo , Fator 2 Relacionado a NF-E2 , Sepse , Animais , Antioxidantes/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Sepse/tratamento farmacológico , Sepse/genética
16.
Food Chem Toxicol ; 166: 113215, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35691465

RESUMO

Oxyberberine (OBB), a main gut-mediated metabolite of Phellodendron chinense Cortex (PC), exhibits prominent protective property against acute liver injury (ALI). Heme oxygenase-1 (HO-1) is a vital molecule in attenuating acute and chronic liver injury for its prominent anti-oxidative injury and anti-inflammation properties. The present study was performed to investigate the hepatoprotective role of OBB through HO-1 signaling pathway in lipopolysaccharide/D-galactosamine (LPS/D-GalN) induced ALI. Our results indicated that PC treatment improved survival rate and its metabolite OBB evidently improved histopathological deteriorations and liver function. Additionally, OBB dramatically ameliorated hepatic oxidative stress and inflammation. Besides, OBB exerted remarkable HO-1 agonistic activity, even be comparable to hemin (a HO-1 inducer), as evidenced by increased HO-1 level, carbon monoxide and bilirubin activities, which are the markers of erythrocyte metabolism. Moreover, OBB modulated the parameters of inflammation and oxidative stress through HO-1 dependent pathway. Beyond this, OBB also notably suppressed the translocation of p65, enhanced antioxidation defense genes expressions, promoted the degradation of Kelch-like ECH-associated protein 1 (Keap1) and the nuclear translocation of nuclear factor-erythroid-2-related factor 2 (Nrf2). In conclusion, OBB could be the principle active metabolite substance of PC and exert excellent hepatoprotective effects via inducing HO-1 through coactivation of erythrocyte metabolism and Nrf2/HO-1 pathway.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Galactosamina , Animais , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Eritrócitos/metabolismo , Galactosamina/toxicidade , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Lipopolissacarídeos/farmacologia , Fígado , Camundongos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Transdução de Sinais
17.
Free Radic Biol Med ; 188: 14-23, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35697292

RESUMO

Flavonoids are widely distributed in plants as secondary metabolites and have various biological benefits such as anti-tumor, anti-oxidant, anti-inflammatory and anti-aging. We previously reported that 4,4'-dimethoxychalcone (DMC) suppressed cancer cell proliferation by aggravating oxidative stress and inducing G2/M cell cycle arrest. In the present study, we explored the underlying mechanisms by which DMC inhibited cancer cell growth. Given that ferrochelatase (FECH) is a potential target of DMC identified by thermal proteome profiling (TPP) method, herein, we confirmed that DMC inhibited the enzymatic activity of FECH. Furthermore, we proved that DMC induced Keap1 degradation via ubiquitin-proteasome system, which led to the nuclear translocation of Nrf2 and upregulated Nrf2 targeted gene HMOX1. FECH inhibition and HMOX1 upregulation resulted in iron overload and triggered ferroptosis in cancer cells. Collectively, we revealed that DMC induced ferroptosis by synergistically activating Keap1/Nrf2/HMOX1 pathway and inhibiting FECH. Our findings indicate that FECH contributes to the non-canonical ferroptosis induction, shed light on the mechanisms of DMC inhibiting cancer cell growth, and set an example for studying biological functions of flavonoids.


Assuntos
Ferroptose , Neoplasias , Antioxidantes/farmacologia , Ferroquelatase/metabolismo , Flavonoides/farmacologia , Fator de Transcrição de Proteínas de Ligação GA , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
18.
Pharmacol Res ; 182: 106310, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35714824

RESUMO

Non-steroidal anti-inflammatory drugs (NSAIDs) relieve inflammation by suppressing prostaglandin E2/cyclooxygenase 2 (PGE2/COX-2) with cardiovascular and gastrointestinal bleeding risk. Theoretically, suppressing PGE2 through inhibiting the terminal synthase microsomal prostaglandin E2 synthase-1 (mPGES-1) instead of upstream COX-2 is ideal for inflammation. Here, (9S,13R)-12-oxo-phytodienoic acid (AA-24) extracted from Artemisia anomala was first screened as an anti-inflammatory candidate and decreased inducible nitric oxide synthase (iNOS), nitric oxide (NO), mPGES-1, and PGE2 without affecting COX-1/2, thromboxane A2 (TXA2) and prostaglandin I2 (PGI2). Besides, AA-24 suppressed the differentiation of M0 macrophages to M1 phenotype but enhanced it to M2 phenotype, blocked the activation of NF-κB pathway, and increased the activation of Nrf2 and heme oxygenase-1 (HO-1). Moreover, AA-24 selectively inhibited mPGES-1 and reduced inflamed paw edema in carrageenan-induced mice. In conclusion, AA-24 attenuates inflammation by inhibiting mPGES-1 and modulating macrophage polarization via the NF-κB and Nrf2/HO-1 pathways and could be a promising candidate for developing anti-inflammatory drugs.


Assuntos
Heme Oxigenase-1 , NF-kappa B , Prostaglandina-E Sintases/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Ácidos Graxos Insaturados , Heme Oxigenase-1/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo
19.
Am J Chin Med ; 50(5): 1349-1360, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35748214

RESUMO

Cornuside (CNS), found in the fruit of Cornus officinalis Seib, is a natural bisiridoid glucoside that possesses therapeutic effects by suppressing inflammation. This study aimed to determine whether CNS could inhibit the inflammatory response induced by lipopolysaccharide (LPS) in human umbilical vein endothelial cells (HUVECs) and mice, as well as to decipher the mechanisms. After activating HUVECs with LPS, the cells were treated with CNS. Cells were then isolated for protein or mRNA assays to analyze signaling and inflammatory molecules. In addition, mice received an intraperitoneal injection of LPS, followed by an intravenously administered dose of CNS. CNS inhibited cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) expressions induced by LPS. CNS decreased phosphorylated signal transducer and activator of transcription 1 (STAT1)-1 by promoting HO-1 expression, inhibiting nuclear factor (NF)-[Formula: see text]B-luciferase activity, and decreasing COX-2/prostaglandin E2 (PGE2) and iNOS/NO. Furthermore, CNS treatment in LPS-activated HUVECs increased the nuclear translocation of nuclear factor erythrocyte 2-related factor 2 (Nrf2) and combined Nrf2 to anti-oxidant response elements and decreased IL-1[Formula: see text] production. Reduced iNOS/NO expression by CNS was restored when HO-1 RNAi inhibited heme oxygenase-1 (HO-1). After CNS treatment in vivo, iNOS levels in lung tissue and tumor necrosis factor (TNF)-[Formula: see text] expression in the bronchoalveolar lavage fluid were significantly decreased. The results indicated that CNS increased HO-1 expression, reduced LPS-activated NF-[Formula: see text]B-luciferase activity, and inhibited iNOS/NO and COX-2/PGE2, all of which contributed to the inhibition of STAT-1 phosphorylation. Thus, CNS can be a potential new substance for treating inflammatory disorders.


Assuntos
Heme Oxigenase-1 , Fator 2 Relacionado a NF-E2 , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Glucosídeos , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Lipopolissacarídeos/farmacologia , Luciferases/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Piranos
20.
Sci Rep ; 12(1): 9986, 2022 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-35705592

RESUMO

Widespread application of carbendazim (CBZ) is a major environmental impact because of its residues that caused multi-organ dysfunction. Recently, Chitosan nanoparticles (CS-NPs) are extensively used as nanocarriers due to their non-toxic and biodegradable nature. Therefore, the current study aimed to investigate the possible mechanistic pathway of modified CS-NPs to reduce the hepatic and nephrotoxicity of CBZ in rats. CS-NPs were synthesized by the ionic gelation method by using ascorbic acid instead of acetic acid to increase its antioxidant efficiency. Twenty-adult male Wistar rats were grouped (n = 5) as follows: Group (1) negative control, group (2) received CS-NPs, group (3) received CBZ, and group (4) co-administered CS-NPs with CBZ. Rats received the aforementioned materials daily by oral gavage for 28 days and weighed weekly. The results revealed that CBZ receiving group showed severe histopathological alterations in the liver and kidney sections including cellular necrosis and interstitial inflammation confirmed by immunostaining and showed marked immunopositivity of iNOS and caspase-3 protein. There were marked elevations in the serum levels of ALT, AST, urea, and creatinine with a significant increase in MDA levels and decrease in TAC levels. Upregulation of the Keap1 gene and down-regulation of Nrf2 and HO-1 genes were also observed. Co-treatment of rats by CS-NPs with CBZ markedly improved all the above-mentioned toxicological parameters and return liver and kidney tissues to normal histological architecture. We concluded that CBZ caused hepatorenal toxicity via oxidative stress and the Nrf2/HO-1 pathway and CS-NPs could reduce CBZ toxicity via their antioxidant, anti-apoptotic, and anti-inflammatory effects.


Assuntos
Quitosana , Rim , Fígado , Nanopartículas , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Benzimidazóis/toxicidade , Carbamatos/toxicidade , Quitosana/química , Quitosana/farmacologia , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Nanopartículas/química , Estresse Oxidativo , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
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