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1.
Int J Mol Sci ; 25(13)2024 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-39000568

RESUMO

Osteoarthritis (OA) is the most common joint disease, causing symptoms such as joint pain, swelling, and deformity, which severely affect patients' quality of life. Despite advances in medical treatment, OA management remains challenging, necessitating the development of safe and effective drugs. Quercetin (QUE), a natural flavonoid widely found in fruits and vegetables, shows promise due to its broad range of pharmacological effects, particularly in various degenerative diseases. However, its role in preventing OA progression and its underlying mechanisms remain unclear. In this study, we demonstrated that QUE has a protective effect against OA development both in vivo and in vitro, and we elucidated the underlying molecular mechanisms. In vitro, QUE inhibited the expression of IL-1ß-induced chondrocyte matrix metalloproteinases (MMP3 and MMP13) and inflammatory mediators such as INOS and COX-2. It also promoted the expression of collagen II, thereby preventing the extracellular matrix (ECM). Mechanistically, QUE exerts its protective effect on chondrocytes by activating the SIRT1/Nrf-2/HO-1 and inhibiting chondrocyte ferroptosis. Similarly, in an OA rat model induced by anterior cruciate ligament transection (ACLT), QUE treatment improved articular cartilage damage, reduced joint pain, and normalized abnormal subchondral bone remodeling. QUE also reduced serum IL-1ß, TNF-α, MMP3, CTX-II, and COMP, thereby slowing the progression of OA. QUE exerts chondroprotective effects by inhibiting chondrocyte oxidative damage and ferroptosis through the SIRT1/Nrf-2/HO-1 pathway, effectively alleviating OA progression in rats.


Assuntos
Cartilagem Articular , Condrócitos , Modelos Animais de Doenças , Ferroptose , Fator 2 Relacionado a NF-E2 , Osteoartrite , Quercetina , Sirtuína 1 , Animais , Sirtuína 1/metabolismo , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Osteoartrite/patologia , Ratos , Quercetina/farmacologia , Quercetina/uso terapêutico , Fator 2 Relacionado a NF-E2/metabolismo , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Ferroptose/efeitos dos fármacos , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/patologia , Cartilagem Articular/metabolismo , Masculino , Transdução de Sinais/efeitos dos fármacos , Ratos Sprague-Dawley , Interleucina-1beta/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo
2.
PLoS One ; 19(7): e0306926, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38990890

RESUMO

The primary objective of this work was to delve into the potential therapeutic advantages and dissect the molecular mechanisms of salidroside in enhancing erectile function in rats afflicted with diabetic microvascular erectile dysfunction (DMED), addressing both the whole-animal and cellular dimensions.We established a DMED model in Sprague‒Dawley (SD) rats and conducted in vivo experiments. The DMED rats were administered varying doses of salidroside, the effects of which on DMED were compared. Erectile function was evaluated by applying electrical stimulation to the cavernous nerves and measuring intracavernous pressure in real time. The penile tissue underwent histological examination and Western blotting. Hydrogen peroxide (H2O2) was employed in the in vitro trial to induce an oxidative stress for the purpose of identifying alterations in cell viability. The CCK-8 assay was used to measure the viability of corpus cavernous smooth muscle cells (CCSMCs) treated with vs. without salidroside. Flow cytometry was utilized to detect alterations in intracellular reactive oxygen species (ROS). Apoptosis was assessed through Western blotting and TdT-mediated dUTP nick-end labelling (TUNEL). Animal and cellular experiments indicate that the Nrf2/HO-1 signalling pathway may be upregulated by salidroside, leading to the improvement of erectile function in diabetic male rats by alleviating oxidative stress and reducing apoptosis in corpus cavernosum tissue.


Assuntos
Apoptose , Disfunção Erétil , Glucosídeos , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Fenóis , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio , Transdução de Sinais , Animais , Masculino , Estresse Oxidativo/efeitos dos fármacos , Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/metabolismo , Disfunção Erétil/etiologia , Apoptose/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Fenóis/farmacologia , Fenóis/uso terapêutico , Glucosídeos/farmacologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/tratamento farmacológico , Pênis/efeitos dos fármacos , Pênis/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Heme Oxigenase (Desciclizante)/metabolismo , Heme Oxigenase-1/metabolismo , Sobrevivência Celular/efeitos dos fármacos
3.
Arch Biochem Biophys ; 758: 110084, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38971420

RESUMO

Nuclear factor erythroid factor 2 (Nrf2) is the key regulatory of the antioxidant response elements. Also, Nrf2 interacts with nuclear factor kappa B (NF-ĸB) to inhibit subsequent inflammatory cascade. Activation of Nrf2 signaling ameliorates drug-induced liver injury. Sodium valproate (SVP) is an anti-epilepsy drug with a hepatotoxic adverse effect that restricts its clinical use. In this study, coadministration of Dihydromyricetin (DHM), a natural flavonoid, with SVP to rats upregulated gene expression of Nrf2 and its downstream gene, heme oxygenase 1 (HO-1), while suppressed the Nrf2 repressor, Keap-1. Additionally, DHM led to downregulation of proinflammatory factors in liver tissues, including NF-ĸB, interleukin 1 beta (IL-1ß), and tumor necrosis factor alpha (TNF-α). This was accompanied by a decrease in the proapoptotic protein (cleaved caspase-3) expression level. Furthermore, biochemical and histopathological studies showed that DHM treatment improved liver function and lipid profile while decreased inflammatory cell infiltration, congestion, and hepatocellular damage. According to our knowledge, prior research has not examined the protective effect of DHM on the liver injury induced by SVP. Consequently, this study provides DHM as a promising herbal medication that, when used with SVP, can prevent its induced hepatotoxicity owing to its potential anti-oxidative, anti-inflammatory, and anti-apoptotic properties.


Assuntos
Caspase 3 , Doença Hepática Induzida por Substâncias e Drogas , Flavonóis , Proteína 1 Associada a ECH Semelhante a Kelch , Fator 2 Relacionado a NF-E2 , NF-kappa B , Transdução de Sinais , Ácido Valproico , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Masculino , Transdução de Sinais/efeitos dos fármacos , Flavonóis/farmacologia , NF-kappa B/metabolismo , Ácido Valproico/farmacologia , Ratos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/patologia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Caspase 3/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Ratos Sprague-Dawley , Heme Oxigenase (Desciclizante)/metabolismo , Heme Oxigenase-1/metabolismo
4.
J Cell Mol Med ; 28(13): e18386, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38990057

RESUMO

Acute lung injury (ALI) is a major pathophysiological problem characterized by severe inflammation, resulting in high morbidity and mortality. Plumbagin (PL), a major bioactive constituent extracted from the traditional Chinese herb Plumbago zeylanica, has been shown to possess anti-inflammatory and antioxidant pharmacological activities. However, its protective effect on ALI has not been extensively studied. The objective of this study was to investigate the protective effect of PL against ALI induced by LPS and to elucidate its possible mechanisms both in vivo and in vitro. PL treatment significantly inhibited pathological injury, MPO activity, and the wet/dry ratio in lung tissues, and decreased the levels of inflammatory cells and inflammatory cytokines TNF-α, IL-1ß, IL-6 in BALF induced by LPS. In addition, PL inhibited the activation of the PI3K/AKT/mTOR signalling pathway, increased the activity of antioxidant enzymes CAT, SOD, GSH and activated the Keap1/Nrf2/HO-1 signalling pathway during ALI induced by LPS. To further assess the association between the inhibitory effects of PL on ALI and the PI3K/AKT/mTOR and Keap1/Nrf2/HO-1 signalling, we pretreated RAW264.7 cells with 740Y-P and ML385. The results showed that the activation of PI3K/AKT/mTOR signalling reversed the protective effect of PL on inflammatory response induced by LPS. Moreover, the inhibitory effects of PL on the production of inflammatory cytokines induced by LPS also inhibited by downregulating Keap1/Nrf2/HO-1 signalling. In conclusion, the results indicate that the PL ameliorate LPS-induced ALI by regulating the PI3K/AKT/mTOR and Keap1-Nrf2/HO-1 signalling, which may provide a novel therapeutic perspective for PL in inhibiting ALI.


Assuntos
Lesão Pulmonar Aguda , Proteína 1 Associada a ECH Semelhante a Kelch , Lipopolissacarídeos , Fator 2 Relacionado a NF-E2 , Naftoquinonas , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Serina-Treonina Quinases TOR , Animais , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Lipopolissacarídeos/efeitos adversos , Lipopolissacarídeos/toxicidade , Naftoquinonas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Camundongos , Masculino , Citocinas/metabolismo , Heme Oxigenase-1/metabolismo , Células RAW 264.7 , Anti-Inflamatórios/farmacologia , Heme Oxigenase (Desciclizante)/metabolismo , Proteínas de Membrana/metabolismo
5.
Immun Inflamm Dis ; 12(6): e1169, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38860757

RESUMO

INTRODUCTION: We aimed to explore the molecular mechanisms through which platelet-rich plasma (PRP) attenuates osteoarthritis (OA)-induced pain, apoptosis, and inflammation. METHODS: An in vivo model of OA was established by injuring rats using the anterior cruciate ligament transection method, whereas an in vitro model was generated by exposing chondrocytes to interleukin (IL)-1ß. Both models were then treated with PRP. RESULTS: In both the in vivo and in vitro models, OA led to the suppression of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway, whereas treatment with PRP reactivated this molecular axis. Inhibition of the Nrf2/HO-1 pathway using the Nrf2 inhibitor brusatol or through Nrf2 gene silencing counteracted the effects of PRP in reducing the tenderness and thermal pain thresholds of OA rats. Additionally, PRP reduced the mRNA expression of IL-1ß, IL-6, tumor necrosis factor-alpha (TNF-α), and matrix metallopeptidase 13 (MMP-13) and the protein expression of B-cell lymphoma 2 (Bcl-2), Bcl-2 associated X-protein (Bax), and caspase-3. Furthermore, inflammation and apoptosis were induced by brusatol treatment or Nrf2 silencing. Additionally, in the in vitro model, PRP treatment increased the proliferation of chondrocytes and attenuated their inflammatory response and apoptosis, effects that were abrogated by Nrf2 depletion. CONCLUSIONS: The Nrf2/HO-1 pathway participates in the PRP-mediated attenuation of OA development by suppressing inflammation and apoptosis.


Assuntos
Apoptose , Condrócitos , Fator 2 Relacionado a NF-E2 , Osteoartrite , Plasma Rico em Plaquetas , Transdução de Sinais , Animais , Osteoartrite/terapia , Osteoartrite/metabolismo , Osteoartrite/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Ratos , Condrócitos/metabolismo , Masculino , Anti-Inflamatórios/farmacologia , Quassinas/farmacologia , Quassinas/uso terapêutico , Ratos Sprague-Dawley , Modelos Animais de Doenças , Heme Oxigenase-1/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase (Desciclizante)/metabolismo , Heme Oxigenase (Desciclizante)/genética , Interleucina-1beta/metabolismo , Inflamação/imunologia , Células Cultivadas
6.
Artigo em Inglês | MEDLINE | ID: mdl-38847145

RESUMO

BACKGROUND: Macrovascular lesions are the main cause of death and disability in diabetes mellitus, and excessive accumulation of cholesterol and lipids can lead to long-term and repeated damage of vascular endothelial cells. Umbilical cord mesenchymal stem cells (UCMSCs) can attenuate vascular endothelial damage in type 1 diabetic mice, while Fufang Xueshuantong capsule (FXC) has a protective effect on endothelial function; however, whether FXC in combination with UCMSCs can improve T2DM macrovascular lesions as well as its mechanism of action are not clear. Therefore, the aim of this study was to reveal the role of FXC + UCMSCs in T2DM vasculopathy and their potential mechanism in the treatment of T2DM. METHODS: The control and T2DM groups were intragastrically administered with equal amounts of saline, the UCMSCs group was injected with UCMSCs (1×106, resuspended cells with 0.5 mL PBS) in the tail vein, the FXC group was intragastrically administered with 0.58 g/kg FXC, and the UCMSCs + FXC group was injected with UCMSCs (1×106) in the tail vein, followed by FXC (0.58 g/kg), for 8 weeks. RESULTS: We found that FXC+UCMSCs effectively reduced lipid levels (TG, TC, and LDL-C) and ameliorated aortic lesions in T2DM rats. Meanwhile, Nrf2 and HO-1 expression were upregulated. We demonstrated that inhibition of Nrf-2 expression blocked the inhibitory effect of FXC+UCMSCs-CM on apoptosis and oxidative stress injury. CONCLUSION: Our data suggest that FXC+UCMSCs may attenuate oxidative stress injury and macroangiopathy in T2DM by activating the Nrf-2/HO-1 pathway.


Assuntos
Diabetes Mellitus Experimental , Medicamentos de Ervas Chinesas , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Ratos Sprague-Dawley , Transdução de Sinais , Animais , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Ratos , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Transplante de Células-Tronco Mesenquimais/métodos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Cordão Umbilical/citologia , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/prevenção & controle , Angiopatias Diabéticas/tratamento farmacológico , Angiopatias Diabéticas/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Heme Oxigenase (Desciclizante)/metabolismo , Terapia Combinada/métodos , Células Cultivadas
7.
Exp Cell Res ; 440(1): 114127, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38857839

RESUMO

CCAAT enhancer binding protein delta (CEBPD) is a transcription factor and plays an important role in apoptosis and oxidative stress, which are the main pathogenesis of ischemic stroke. However, whether CEBPD regulates ischemic stroke through targeting apoptosis and oxidative stress is unclear. Therefore, to answer this question, rat middle cerebral artery occlusion (MCAO) reperfusion model and oxygen-glucose deprivation/reoxygenation (OGD/R) primary cortical neuron were established to mimic ischemic reperfusion injury. We found that CEBPD was upregulated and accompanied with increased neurological deficit scores and infarct size, and decreased neuron in MCAO rats. The siRNA targeted CEBPD inhibited CEBPD expression in rats, and meanwhile lentivirus system was used to blocked CEBPD expression in primary neuron. CEBPD degeneration decreased neurological deficit scores, infarct size and brain water content of MCAO rats. Knockdown of CEBPD enhanced cell viability and reduced apoptosis as well as oxidative stress in vivo and in vitro. CEBPD silencing promoted the translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) to the nucleus and the expression of heme oxygenase 1 (HO-1). Newly, CEBPD facilitated the transcription of cullin 3 (CUL3), which intensified ischemic stroke through Nrf2/HO-1 pathway that was proposed by our team in the past. In conclusion, targeting CEBPD-CUL3-Nrf2/HO-1 axis may be contributed to cerebral ischemia therapy.


Assuntos
Apoptose , Heme Oxigenase-1 , AVC Isquêmico , Fator 2 Relacionado a NF-E2 , Neurônios , Estresse Oxidativo , Ratos Sprague-Dawley , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Neurônios/metabolismo , Neurônios/patologia , AVC Isquêmico/metabolismo , AVC Isquêmico/patologia , Ratos , Masculino , Heme Oxigenase-1/metabolismo , Heme Oxigenase-1/genética , Proteína delta de Ligação ao Facilitador CCAAT/metabolismo , Proteína delta de Ligação ao Facilitador CCAAT/genética , Transdução de Sinais , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Heme Oxigenase (Desciclizante)
8.
Pharmazie ; 79(6): 101-108, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38877681

RESUMO

In this study, we hypothesized that lixisenatide (LIX) and ticagrelor (TIC) could have a protective effect against type 2 diabetes mellitus (T2DM)-induced vascular damage. Furthermore, we explored the possible additional protective effect of co-administering LIX and TIC in the treatment regimen. Methods: 50 male rats were divided into five groups, each comprising 10 rats: C (control), D (T2DM rats), D + LIX (T2DM rats treated with LIX for 4 weeks), D + TIC (T2DM rats treated with TIC for 4 weeks), and D + LIX + TIC (T2DM rats treated with LIX + TIC for 4 weeks). Results: The D group showed an increase in body weight, blood glucose, hemostatic model assessment for insulin resistance (HOMA-IR), aorta reactive oxygen species (ROS), and nuclear factor kappa B (NF-κ B), along with a reduction in serum insulin, aorta superoxide dismutase (SOD), glutathione reduced (GSH), nuclear factor erythroid-2 (NrF2), hemeoxygenase-1 (HO-1), and endothelial nitric oxide synthase (eNOS). Deterioration in the aorta histopathological condition, coupled with a noticeable impairment in vascular reactivity compared to the C group, was observed. A single administration of LIX showed a reduction in body weight, blood glucose, HOMA-IR, aorta ROS, and NF-κ B, accompanied by an increase in serum insulin, aorta SOD, GSH, NrF2, HO-1, and eNOS. Amelioration in the aorta histopathological condition and improved vascular reactivity compared to the D group were reported. Similarly, a single administration of TIC showed a reduction in aorta ROS and NF-κ B, along with an increase in aorta SOD, GSH, NrF2, HO-1, and eNOS. A slight amelioration was detected in the aorta histopathological condition, with improved vascular reactivity compared to the D group. The combined administration of LIX and TIC showed a reduction in aorta ROS and NF-κ B, along with an increase in aorta GSH, SOD, HO-1, and eNOS. This was combined with evident amelioration in the aorta histopathological condition and noticeable improvement in vascular reactivity compared to the single treatment with either LIX or TIC group. Conclusion: The present study introduces clear evidence that the administration of LIX and TIC can improve metabolic and vascular complications of T2DM through modulating eNOS and NrF2 /HO-1 signaling. The combined administration of LIX and TIC produced more significant effects than a single treatment.


Assuntos
Diabetes Mellitus Experimental , Fator 2 Relacionado a NF-E2 , Óxido Nítrico Sintase Tipo III , Peptídeos , Espécies Reativas de Oxigênio , Transdução de Sinais , Ticagrelor , Animais , Masculino , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Ticagrelor/farmacologia , Ticagrelor/administração & dosagem , Peptídeos/farmacologia , Peptídeos/administração & dosagem , Fator 2 Relacionado a NF-E2/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Espécies Reativas de Oxigênio/metabolismo , Glicemia/efeitos dos fármacos , Resistência à Insulina , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Ratos Sprague-Dawley , Heme Oxigenase (Desciclizante)/metabolismo , NF-kappa B/metabolismo , Hipoglicemiantes/farmacologia , Hipoglicemiantes/administração & dosagem , Heme Oxigenase-1/metabolismo , Insulina , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Sinergismo Farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 2
9.
Food Chem Toxicol ; 190: 114796, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38852756

RESUMO

Pulmonary fibrosis is the outcome of the prolonged interstitial pneumonia, characterized by excessive accumulation of fibroblasts and collagen deposition, leading to its development. This study aimed to study the changes in PI3K/AKT and NRF2/HO-1 signaling expression and intestinal microbiota in a rat model of a novel bleomycin-induced pulmonary fibrosis. The findings of our study showed the model was successfully established. The results showed that the alveolar septum in the model was significantly widened and infiltrated by severe inflammatory cells. Alveolar atrophy occurred due to the formation of multiple inflammatory foci. During this period, fibrous tissue was distributed in strips and patches, primarily around the pulmonary interstitium and bronchus. Moreover, lung damage and fibrosis progressively worsened over time. The mRNA expression of HO-1 and NRF2 in the model decreased while the mRNA expression of HIF-1α, VEGF, PI3K and AKT increased. Furthermore, it was observed to decrease the protein expression of E-cad, HO-1 and NRF2, and increase the protein expression of α-SMA and p-AKT. Additionally, this model leaded to an imbalance in the intestinal microbiota. This study demonstrate that the novel pulmonary fibrosis model activates the NRF2/HO-1 pathway and the PI3K/AKT pathway in rat lung tissues, and leading to intestinal barrier disorder.


Assuntos
Bleomicina , Microbioma Gastrointestinal , Fator 2 Relacionado a NF-E2 , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Fibrose Pulmonar , Transdução de Sinais , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Bleomicina/toxicidade , Bleomicina/efeitos adversos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/genética , Masculino , Ratos , Ratos Sprague-Dawley , Heme Oxigenase (Desciclizante)/metabolismo , Heme Oxigenase (Desciclizante)/genética , Heme Oxigenase-1/metabolismo , Heme Oxigenase-1/genética
10.
Int Immunopharmacol ; 136: 112380, 2024 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-38850790

RESUMO

BACKGROUND AND AIMS: Impaired intestinal barrier function is key in maintaining intestinal inflammation in Crohn's disease (CD). However, no targeted treatment in clinical practice has been developed. Peiminine (Pm) strongly protects the epithelial barrier, the purpose of this study is to investigate whether Pm affects CD-like colitis and potential mechanisms for its action. METHODS: Trinitro-benzene-sulfonic acid (TNBS)-induced mice and Il-10-/- mice were used as CD animal models. Colitis symptoms, histological analysis, and intestinal barrier permeability were used to assess the Pm's therapeutic effect on CD-like colitis. The colon organoids were induced by TNF-α to evaluate the direct role of Pm in inhibiting apoptosis of the intestinal epithelial cells. Western blotting and small molecule inhibitors were used to investigate further the potential mechanism of Pm in inhibiting apoptosis of intestinal epithelial cells. RESULTS: Pm treatment reduced body weight loss, disease activity index (DAI) score, and inflammatory score, demonstrating that colonic inflammation in mice were alleviated. Pm decreased the intestinal epithelial apoptosis, improved the intestinal barrier function, and prevented the loss of tight junction proteins (ZO1 and claudin-1) in the colon of CD mice and TNF-α-induced colonic organoids. Pm activated Nrf2/HO1 signaling, which may protect intestinal barrier function. CONCLUSIONS: Pm inhibits intestinal epithelial apoptosis in CD mice by activating Nrf2/HO1 pathway. This partially explains the potential mechanism of Pm in ameliorating intestinal barrier function in mice and provides a new approach to treating CD.


Assuntos
Apoptose , Colite , Doença de Crohn , Modelos Animais de Doenças , Mucosa Intestinal , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2 , Transdução de Sinais , Ácido Trinitrobenzenossulfônico , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Doença de Crohn/tratamento farmacológico , Doença de Crohn/patologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Mucosa Intestinal/metabolismo , Colite/tratamento farmacológico , Colite/induzido quimicamente , Colite/patologia , Camundongos , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Humanos , Masculino , Colo/patologia , Colo/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase (Desciclizante)/metabolismo , Heme Oxigenase (Desciclizante)/genética , Interleucina-10/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Proteínas de Membrana
11.
Biomed Pharmacother ; 176: 116854, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38824834

RESUMO

BACKGROUND: Acute pancreatitis (APS) is a prevalent acute pancreatic inflammation, where oxidative stress, inflammatory signaling pathways, and apoptosis activation contribute to pancreatic injury. METHODS: Pinocembrin, the predominant flavonoid in propolis, was explored for its likely shielding effect against APS provoked by two intraperitoneal doses of L-arginine (250 mg / 100 g) in a rat model. RESULTS: Pinocembrin ameliorated the histological and immunohistochemical changes in pancreatic tissues and lowered the activities of pancreatic amylase and lipase that were markedly elevated with L-arginine administration. Moreover, pinocembrin reinstated the oxidant/antioxidant equilibrium, which was perturbed by L-arginine, and boosted the pancreatic levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Pinocembrin markedly reduced the elevation in serum C-reactive protein (CRP) level induced by L-arginine. Additionally, it decreased the expression of high motility group box protein 1 (HMGB1), toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and NOD-like receptor (NLR) Family Pyrin Domain Containing 3 (NLRP3) inflammasome in the pancreas. Furthermore, it also reduced myeloperoxidase (MPO) activity. Pinocembrin markedly downregulated miR-34a-5p expression and upregulated the protein levels of peroxisome proliferator-activated receptor alpha (PPAR-α) and Sirtuin 1 (SIRT1) and the gene expression level of the inhibitor protein of NF-κB (IκB-α), along with normalizing the Bax/Bcl-2 ratio. CONCLUSIONS: Pinocembrin notably improved L-arginine-induced APS by its antioxidant, anti-inflammatory, and anti-apoptotic activities. Pinocembrin exhibited a protective role in APS by suppressing inflammatory signaling via the TLR4/NF-κB/NLRP3 pathway and enhancing cytoprotective signaling via the miR-34a-5p/SIRT1/Nrf2/HO-1 pathway.


Assuntos
Modelos Animais de Doenças , Flavanonas , Heme Oxigenase (Desciclizante) , MicroRNAs , Fator 2 Relacionado a NF-E2 , NF-kappa B , Proteína 3 que Contém Domínio de Pirina da Família NLR , Pancreatite , Ratos Sprague-Dawley , Transdução de Sinais , Sirtuína 1 , Receptor 4 Toll-Like , Animais , Pancreatite/induzido quimicamente , Pancreatite/prevenção & controle , Pancreatite/metabolismo , Pancreatite/patologia , Pancreatite/tratamento farmacológico , Sirtuína 1/metabolismo , NF-kappa B/metabolismo , Receptor 4 Toll-Like/metabolismo , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , MicroRNAs/metabolismo , MicroRNAs/genética , Flavanonas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ratos , Heme Oxigenase (Desciclizante)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Arginina/farmacologia , Doença Aguda , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Pâncreas/metabolismo , Antioxidantes/farmacologia , Estresse Oxidativo/efeitos dos fármacos
12.
Int Immunopharmacol ; 137: 112439, 2024 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-38870884

RESUMO

Ischemic stroke is acknowledged as one of the most frequent causes of death and disability, in which neuroinflammation plays a critical role. Emerging evidence supports that the PGK1/Nrf2/HO-1 signaling can modulate inflammation and oxidative injury. Albiflorin (ALB), a main component of Radix paeoniae Alba, possesses anti-inflammatory and antioxidative properties. However, how it exerts a protective role still needs further exploration. In our study, the middle cerebral artery occlusion (MCAO) model was established, and the Longa score was applied to investigate the degree of neurological impairment. Dihydroethidium (DHE) staining and Malondialdehyde (MDA) assay were used to detect the level of lipid peroxidation. 2, 3, 5-Triphenyltetrazolium chloride (TTC) staining was used to measure the infarct area. Evans blue staining was employed to observe the integrality of the blood-brain barrier (BBB). The injury of brain tissue in each group was observed via HE staining. Immunofluorescence staining, enzyme-linked immunosorbent assay (ELISA) and western blot assay were used for the measurement of inflammatory factors and protein levels. We finally observed that ALB relieved cerebral infarction symptoms, attenuated oxidative damage in brain tissues, and reduced neuroinflammation and cell injury in MCAO rats. The overexpression of PGK1 abrogated the protective effect of ALB after experimental cerebral infarction. ALB promoted PGK1 degradation and induced Nrf2 signaling cascade activation for subsequent anti-inflammatory and antioxidant damage. Generally speaking, ALB exerted a protective role in treating cerebral ischemia, and it might target at PGK1/Nrf2/HO-1 signaling. Thus, ALB might be a potential therapeutic agent to alleviate neuroinflammation and protect brain cells after cerebral infarction.


Assuntos
Anti-Inflamatórios , Infarto da Artéria Cerebral Média , Fator 2 Relacionado a NF-E2 , Fosfoglicerato Quinase , Ratos Sprague-Dawley , Transdução de Sinais , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Masculino , Transdução de Sinais/efeitos dos fármacos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/patologia , Ratos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Fosfoglicerato Quinase/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Doenças Neuroinflamatórias/tratamento farmacológico , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Modelos Animais de Doenças , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/metabolismo , Humanos , Heme Oxigenase (Desciclizante)/metabolismo , Hidrocarbonetos Aromáticos com Pontes
13.
Int Immunopharmacol ; 137: 112450, 2024 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-38906007

RESUMO

Inflammation, apoptosis and oxidative stress play crucial roles in the deterioration of severe acute pancreatitis-associated acute respiratory distress syndrome (SAP-ARDS). Unfortunately, despite a high mortality rate of 45 %[1], there are limited treatment options available for ARDS outside of last resort options such as mechanical ventilation and extracorporeal support strategies[2]. This study investigated the potential therapeutic role and mechanisms of AQP9 inhibitor RG100204 in two animal models of severe acute pancreatitis, inducing acute respiratory distress syndrome: 1) a sodium-taurocholate induced rat model, and 2) and Cerulein and lipopolysaccharide induced mouse model. RG100204 treatment led to a profound reduction in inflammatory cytokine expression in pancreatic, and lung tissue, in both models. In addition, infiltration of CD68 + and CD11b + cells into these tissues were reduced in RG100204 treated SAP animals, and edema and SAP associated tissue damage were improved. Moreover, we demonstrate that RG100204 reduced apoptosis in the lungs of rat SAP animals, and reduces NF-κB signaling, NLRP3, expression, while profoundly increasing the Nrf2-dependent anti oxidative stress response. We conclude that AQP9 inhibition is a promising strategy for the treatment of pancreatitis and its systemic complications, such as ARDS.


Assuntos
Fator 2 Relacionado a NF-E2 , Proteína 3 que Contém Domínio de Pirina da Família NLR , Pancreatite , Síndrome do Desconforto Respiratório , Transdução de Sinais , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Pancreatite/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Masculino , Transdução de Sinais/efeitos dos fármacos , Camundongos , Ratos , Síndrome do Desconforto Respiratório/tratamento farmacológico , Síndrome do Desconforto Respiratório/metabolismo , Aquaporinas/metabolismo , Aquaporinas/antagonistas & inibidores , Modelos Animais de Doenças , Ratos Sprague-Dawley , Pulmão/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Ácido Taurocólico , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Pâncreas/patologia , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Ceruletídeo , Humanos , Heme Oxigenase (Desciclizante)/metabolismo
14.
J Ethnopharmacol ; 333: 118505, 2024 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-38945466

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Zuogui Pill (ZGP) is a traditional herbal formula of Chinese Medicine with a long history of use in alleviating ovarian aging. AIM OF THE STUDY: To examine the impact of ZGP on oxidative stress and the stemness of oogonial stem cells (OSCs) in cyclophosphamide (CTX)-induced ovarian aging, as well as its molecular mechanisms involving the nuclear factor erythroid 2-related factor 2 (Nrf2, NFE2L2)/heme oxygenase-1 (HO-1, Hmox1) pathway. MATERIALS AND METHODS: Female Sprague-Dawley (SD) rats were randomly divided into seven groups: control, model (CTX), estradiol valerate (EV, 0.103 mg/kg), ZGP-L (low dose Zuogui Pill, 1.851 g/kg), ZGP-H (high dose Zuogui Pill, 3.702 g/kg), ML385 (30 mg/kg), and ML385+ZGP-L. After CTX modeling, the EV, ZGP-L, ZGP-H, and ML385+ZGP-L groups were treated by gavage for 8 weeks, while the ML385 and ML385+ZGP-L groups were administered the Nrf2 antagonist ML385 twice a week. OSCs were isolated after modeling and then treated with drug serum containing 10% ZGP or 10 µM ML385. The general conditions of the rats, including body weight, ovarian weight/body weight ratio, and estrous cycle, were observed. Ovarian ultrastructure, follicle and corpus luteum counts were assessed via hematoxylin and eosin (H&E) staining. Serum hormone levels were measured using enzyme-linked immunosorbent assay (ELISA). Nrf2/HO-1 pathway, stem cell, germ cell, and cell cycle biomarkers were analyzed by qPCR and Western blot. Cell viability was assessed by cell counting kit-8 (CCK-8) assay. Oxidative stress biomarkers were evaluated using flow cytometry and assay kits. Immunofluorescence was employed to detect and locate OSCs in the ovary, quantify the average fluorescence intensity, and identify OSCs. RESULTS: After ZGP treatment, rats with CTX-induced ovarian aging exhibited improved general condition, increased body weight, higher total ovarian weight to body weight ratio, and a restoration of the estrous cycle similar to the control group. Serum levels of estradiol (E2) and follicle stimulating hormone (FSH), two sex hormones, were also improved. Ovarian ultrastructure and follicle count at all stages showed improvement. Moreover, the viability and proliferation capacity of OSCs were enhanced following ZGP intervention. The Nrf2/HO-1 pathway was found to be down-regulated in CTX-induced aging ovarian OSCs. However, ZGP reversed this effect by activating the expression of Nrf2, HO-1, and NAD(P)H oxidoreductase 1 (NQO1), increasing the activity of antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX), and reducing the accumulation of malonaldehyde (MDA) and reactive oxygen species (ROS), thus restoring resistance to oxidative stress. Additionally, ZGP improved the cell cycle of OSCs, up-regulated the expression of Cyclin D1 and Cyclin E1, restored cell stemness, promoted proliferation, enhanced the expression of cell stemness markers octamer-binding transcription factor 4 (Oct4) and mouse VASA homolog (MVH), and down-regulated the expression of P21, thereby inhibiting apoptosis. The therapeutic effects of ZGP against oxidative stress and restoration of cell stemness were attenuated following inhibition of the Nrf2 signaling pathway using ML385. CONCLUSIONS: ZGP protected against CTX-induced ovarian aging by restoring normal ovarian function, alleviating oxidative stress in aging OSCs, promoting OSCs proliferation, and restoring their stemness in rats, possibly through regulating the Nrf2/HO-1 pathway.


Assuntos
Ciclofosfamida , Medicamentos de Ervas Chinesas , Fator 2 Relacionado a NF-E2 , Células-Tronco de Oogônios , Ovário , Estresse Oxidativo , Ratos Sprague-Dawley , Transdução de Sinais , Animais , Feminino , Estresse Oxidativo/efeitos dos fármacos , Ciclofosfamida/toxicidade , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Ovário/efeitos dos fármacos , Ovário/metabolismo , Ovário/patologia , Ratos , Células-Tronco de Oogônios/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Envelhecimento/efeitos dos fármacos , Heme Oxigenase (Desciclizante)/metabolismo
15.
Int Immunopharmacol ; 137: 112394, 2024 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-38852517

RESUMO

BACKGROUND: Ferroptosis is a distinct iron-dependent non-apoptotic type of programmed cell death that is implicated in the pathophysiology of rheumatoid arthritis (RA). Although asiatic acid (AA) is documented to have significant anti-inflammatory effects in various diseases, it is not known whether it can regulate RA via ferroptosis. METHODS: The effects of AA on rheumatoid arthritis fibroid-like synoviocytes (RA-FLS) were assessed in vitro, and a rat model of type II collagen-induced arthritis (CIA) was established to evaluate the effectiveness of AA treatment in vivo. RESULTS: AA significantly reduced both viability and colony formation in cultured RA-FLS, while increasing the levels of reactive oxygen species (ROS), ferrous iron (Fe2+), malondialdehyde (MDA), and lactate dehydrogenase (LDH), as well as the expression of COX2. Furthermore, AA induced ferroptosis in RA-FLS by promoting Fe2+ accumulation through downregulation of the expression of Keap1 and FTH1 and upregulation of Nrf2 and HMOX1. In vivo, AA treatment was found to reduce toe swelling and the arthritis score in CIA rats, as well as relieve inflammation and ankle damage and significantly upregulate the expression of Nrf2 and HMOX1 in the synovial fluid. CONCLUSION: Treatment with AA significantly reduced the viability of RA-FLS and triggered ferroptosis by promoting accumulation of Fe2+via the Nrf2-HMOX1 pathway, and was effective in relieving inflammation in CIA model rats. These findings suggest that the use of AA may be a promising strategy for the clinical treatment of RA.


Assuntos
Artrite Experimental , Artrite Reumatoide , Ferroptose , Fator 2 Relacionado a NF-E2 , Triterpenos Pentacíclicos , Transdução de Sinais , Sinoviócitos , Animais , Ferroptose/efeitos dos fármacos , Artrite Reumatoide/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Triterpenos Pentacíclicos/uso terapêutico , Triterpenos Pentacíclicos/farmacologia , Artrite Experimental/tratamento farmacológico , Humanos , Ratos , Transdução de Sinais/efeitos dos fármacos , Sinoviócitos/efeitos dos fármacos , Sinoviócitos/metabolismo , Masculino , Células Cultivadas , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/farmacologia , Heme Oxigenase-1/metabolismo , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Heme Oxigenase (Desciclizante)
16.
World J Gastroenterol ; 30(20): 2709-2725, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38855154

RESUMO

BACKGROUND: Constipation, a highly prevalent functional gastrointestinal disorder, induces a significant burden on the quality of patients' life and is associated with substantial healthcare expenditures. Therefore, identifying efficient therapeutic modalities for constipation is of paramount importance. Oxidative stress is a pivotal contributor to colonic dysmotility and is the underlying pathology responsible for constipation symptoms. Consequently, we postulate that hydrogen therapy, an emerging and promising intervention, can serve as a safe and efficacious treatment for constipation. AIM: To determine whether hydrogen-rich water (HRW) alleviates constipation and its potential mechanism. METHODS: Constipation models were established by orally loperamide to Sprague-Dawley rats. Rats freely consumed HRW, and were recorded their 24 h total stool weight, fecal water content, and charcoal propulsion rate. Fecal samples were subjected to 16S rDNA gene sequencing. Serum non-targeted metabolomic analysis, malondialdehyde, and superoxide dismutase levels were determined. Colonic tissues were stained with hematoxylin and eosin, Alcian blue-periodic acid-Schiff, reactive oxygen species (ROS) immunofluorescence, and immunohistochemistry for cell growth factor receptor kit (c-kit), PGP 9.5, sirtuin1 (SIRT1), nuclear factor-erythroid-2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1). Quantitative real-time PCR and western blot analysis were conducted to determine the expression level of SIRT1, Nrf2 and HO-1. A rescue experiment was conducted by intraperitoneally injecting the SIRT1 inhibitor, EX527, into constipated rats. NCM460 cells were induced with H2O2 and treated with the metabolites to evaluate ROS and SIRT1 expression. RESULTS: HRW alleviated constipation symptoms by improving the total amount of stool over 24 h, fecal water content, charcoal propulsion rate, thickness of the intestinal mucus layer, c-kit expression, and the number of intestinal neurons. HRW modulated intestinal microbiota imbalance and abnormalities in serum metabolism. HRW could also reduce intestinal oxidative stress through the SIRT1/Nrf2/HO-1 signaling pathway. This regulatory effect on oxidative stress was confirmed via an intraperitoneal injection of a SIRT1 inhibitor to constipated rats. The serum metabolites, ß-leucine (ß-Leu) and traumatic acid, were also found to attenuate H2O2-induced oxidative stress in NCM460 cells by up-regulating SIRT1. CONCLUSION: HRW attenuates constipation-associated intestinal oxidative stress via SIRT1/Nrf2/HO-1 signaling pathway, modulating gut microbiota and serum metabolites. ß-Leu and traumatic acid are potential metabolites that upregulate SIRT1 expression and reduce oxidative stress.


Assuntos
Colo , Constipação Intestinal , Hidrogênio , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Transdução de Sinais , Sirtuína 1 , Animais , Humanos , Masculino , Ratos , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Constipação Intestinal/metabolismo , Constipação Intestinal/tratamento farmacológico , Modelos Animais de Doenças , Fezes/química , Heme Oxigenase (Desciclizante)/metabolismo , Heme Oxigenase-1/metabolismo , Hidrogênio/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , Água/metabolismo
17.
Reprod Domest Anim ; 59(6): e14598, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38881434

RESUMO

Our previous research has shown that melatonin (MLT) can reduce cryopreserved ovarian damage in mice. Yet, the molecular mechanism of MLT protection is still unclear. Some studies have shown that melatonin receptor 1 (MT1) is very important for animal reproductive system. To evaluate whether MLT exerts its protective effect on cryopreserved mice ovarian tissue via MT1, we added antagonist of MT1/MT2 (Luzindor) or antagonist of MT2 (4P-PDOT) to the freezing solution, followed by cryopreservation and thawing of ovarian tissue. The levels of total superoxide dismutase (T-SOD), catalase (CAT), nitric oxide (NO) and malondialdehyde (MDA) were detected. Besides, by using RT-PCR and Western blotting, the expression of Bcl-2, Bax and Nrf2/HO-1 signalling pathway-related proteins was detected. These findings demonstrated that compared with the melatonin group, the addition of Luzindor increased apoptosis, NO and MDA activities, decreased CAT and T-SOD activities and inhibited Nrf2/HO-1 signalling pathway. In conclusion, melatonin can play a protective role in cryopreserved ovarian tissue of mice through MT1 receptor.


Assuntos
Criopreservação , Melatonina , Fator 2 Relacionado a NF-E2 , Ovário , Estresse Oxidativo , Receptor MT1 de Melatonina , Transdução de Sinais , Animais , Feminino , Melatonina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ovário/efeitos dos fármacos , Receptor MT1 de Melatonina/metabolismo , Receptor MT1 de Melatonina/genética , Transdução de Sinais/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Camundongos , Criopreservação/veterinária , Triptaminas/farmacologia , Apoptose/efeitos dos fármacos , Heme Oxigenase (Desciclizante)/metabolismo , Heme Oxigenase (Desciclizante)/genética , Óxido Nítrico/metabolismo , Malondialdeído/metabolismo , Proteínas de Membrana , Heme Oxigenase-1
18.
Neurochem Res ; 49(8): 2131-2147, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38822984

RESUMO

BACKGROUND: Sepsis-associated encephalopathy (SAE) develops in 30-70% of hospitalized patients with sepsis. In intensive care units (ICUs), propofol is often administered to ensure an appropriate level of sedation in mechanically ventilated patients. Ferroptosis is a newly identified mode of cellular death characterized by the peroxidation of membrane lipids and excessive iron. This study was conducted to explore the interplay between propofol, sepsis, and ferroptosis. METHODS: An acute systemic inflammatory model was constructed via the intraperitoneal administration of lipopolysaccharide (LPS). Nissl and Fluoro-Jade C (FJC) staining were employed to display neuronal damage and degeneration. Western blotting and immunofluorescence (IF) staining of Bax and Bcl-2 were used to confirm the neural apoptosis. QPCR of cytokines and DHE staining were used to indicate neuroinflammation. To validate ferroptosis, we assessed the content of malondialdehyde (MDA), GSH, and tissue iron, accompanied by transcription level of CHAC1, PTGS2 and GPX4. Additionally, we examined the content of acyl-CoA synthetase long-chain family member 4 (ACSL4), xCT (SLC7A11, solute carrier family 7 member 11), and glutathione peroxidase 4 (GPX4). The IF staining of Iba1-labeled microglia and GFAP-marked astrocytes were used to measure the gliosis. Erastin was pre-pretreated to confirm the anti-ferroptotic capability of propofol. ML385 was preconditioned to explore the role of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in propofol-repressed ferroptosis. RESULTS: Propofol dose-dependently inhibited the decrease of Nissl-positive neurons and the increase of FJC-stained neurons in septic hippocampus and cortex. Neural cytokines, oxidative stress, apoptosis and gliosis were reduced by propofol. Propofol repressed the level of MDA, iron, CHAC1, PTGS2, ACLS4 and restored the content of GSH, GPX4, xCT, Nrf2 and HO-1, thus inhibiting sepsis-induced ferroptosis. All protections from propofol could be reversed by eratsin and ML385 pretreatment. CONCLUSION: Propofol protected against sepsis-induced brain damage, neuroinflammation, neuronal apoptosis and gliosis through the activation of the Nrf2/HO-1 axis to combat ferroptosis.


Assuntos
Ferroptose , Fator 2 Relacionado a NF-E2 , Propofol , Ferroptose/efeitos dos fármacos , Ferroptose/fisiologia , Propofol/farmacologia , Propofol/uso terapêutico , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sepse/metabolismo , Sepse/complicações , Sepse/tratamento farmacológico , Lipopolissacarídeos , Encefalopatia Associada a Sepse/metabolismo , Encefalopatia Associada a Sepse/tratamento farmacológico , Encefalopatia Associada a Sepse/prevenção & controle , Heme Oxigenase-1/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Proteínas de Membrana/metabolismo , Lesões Encefálicas/metabolismo , Lesões Encefálicas/tratamento farmacológico , Coenzima A Ligases , Sistema y+ de Transporte de Aminoácidos
19.
Sci Rep ; 14(1): 11240, 2024 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-38755191

RESUMO

Nao-an Dropping Pill (NADP) is a Chinese patent medicine which commonly used in clinic for ischemic stroke (IS). However, the material basis and mechanism of its prevention or treatment of IS are unclear, then we carried out this study. 52 incoming blood components were resolved by UHPLC-MS/MS from rat serum, including 45 prototype components. The potential active prototype components hydroxysafflor yellow A, ginsenoside F1, quercetin, ferulic acid and caffeic acid screened by network pharmacology showed strongly binding ability with PIK3CA, AKT1, NOS3, NFE2L2 and HMOX1 by molecular docking. In vitro oxygen-glucose deprivation/reperfusion (OGD/R) experimental results showed that NADP protected HA1800 cells from OGD/R-induced apoptosis by affecting the release of LDH, production of NO, and content of SOD and MDA. Meanwhile, NADP could improve behavioral of middle cerebral artery occlusion/reperfusion (MCAO/R) rats, reduce ischemic area of cerebral cortex, decrease brain water and glutamate (Glu) content, and improve oxidative stress response. Immunohistochemical results showed that NADP significantly regulated the expression of PI3K, Akt, p-Akt, eNOS, p-eNOS, Nrf2 and HO-1 in cerebral ischemic tissues. The results suggested that NADP protects brain tissues and ameliorates oxidative stress damage to brain tissues from IS by regulating PI3K/Akt/eNOS and Nrf2/HO-1 signaling pathways.


Assuntos
AVC Isquêmico , Fator 2 Relacionado a NF-E2 , Óxido Nítrico Sintase Tipo III , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/metabolismo , AVC Isquêmico/prevenção & controle , Ratos , Fosfatidilinositol 3-Quinases/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Transdução de Sinais/efeitos dos fármacos , Masculino , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/uso terapêutico , Ratos Sprague-Dawley , Estresse Oxidativo/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Apoptose/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular
20.
J Am Chem Soc ; 146(23): 15955-15964, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38814055

RESUMO

Artificial syntheses of biologically active molecules have been fruitful in many bioinspired catalysis applications. Specifically, verdoheme and biliverdin, bearing polypyrrole frameworks, have inspired catalyst designs to address energy and environmental challenges. Despite remarkable progress in benchtop synthesis of verdoheme and biliverdin derivatives, all reported syntheses, starting from metalloporphyrins or inaccessible biliverdin precursors, require multiple steps to achieve the final desired products. Additionally, such synthetic procedures use multiple reactants/redox agents and involve multistep purification/extraction processes that often lower the yield. However, in a single step using atmospheric oxygen, heme oxygenases selectively generate verdoheme or biliverdin from heme. Motivated by such enzymatic pathways, we report a single-step electrosynthesis of verdoheme or biliverdin derivatives from their corresponding meso-aryl-substituted metalloporphyrin precursors. Our electrosynthetic methods have produced a copper-coordinating verdoheme analog in >80% yield at an applied potential of 0.65 V vs ferrocene/ferrocenium in air-exposed acetonitrile solution with a suitable electrolyte. These electrosynthetic routes reached a maximum product yield within 8 h of electrolysis at room temperature. The major products of verdoheme and biliverdin derivatives were isolated, purified, and characterized using electrospray mass spectrometry, absorption spectroscopy, cyclic voltammetry, and nuclear magnetic resonance spectroscopy techniques. Furthermore, X-ray crystallographic data were collected for select cobalt (Co)- and Cu-chelating verdoheme and metal-free biliverdin products. Electrosynthesis routes for the selective modification at the macrocycle ring in a single step are not known yet, and therefore, we believe that this report would advance the scopes of electrosynthesis strategies.


Assuntos
Biliverdina , Biliverdina/química , Biliverdina/metabolismo , Biliverdina/análogos & derivados , Heme/química , Heme/análogos & derivados , Técnicas Eletroquímicas , Heme Oxigenase (Desciclizante)/metabolismo , Heme Oxigenase (Desciclizante)/química , Porfirinas/química , Estrutura Molecular
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