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1.
Zhongguo Zhong Yao Za Zhi ; 46(1): 24-32, 2021 Jan.
Artículo en Chino | MEDLINE | ID: mdl-33645047

RESUMEN

Nrf2 is the key transcription factor mainly for regulating oxidative homeostasis and cytoprotective responses against oxidative stress. Nrf2/Keap1 pathway is one of the most important cellular defense mechanisms against endogenous or exogenous oxidative stress. With its activation, a wide range of stress-related genes is transactivated to restore the cellular homeostasis. Recent studies revealed that the aberrant activation of Nrf2 is related to the malignant progression, chemotherapeutic drug resistance and poor prognosis. Nrf2 plays a crucial role in cancer malignancy and chemotherapeutic resistance by controlling the intracellular redox homeostasis through the activation of cytoprotective antioxidant genes. Nrf2 inhibitor containing many natural products has been deemed as a novel therapeutic strategy for human malignancies. This article reviews the progress of studies of the Nrf2/Keap1 pathway, and its biological impact in solid malignancies and molecular mechanisms for causing Nrf2 hyperactivation in cancer cells. In conclusion, we summarized the deve-lopment of Nrf2 inhibitors in recent years, in the expectation of providing reference for further drug development and clinical studies.


Asunto(s)
Factor 2 Relacionado con NF-E2 , Neoplasias , Humanos , Proteína 1 Asociada A ECH Tipo Kelch/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Oxidación-Reducción , Estrés Oxidativo
2.
Zhongguo Zhen Jiu ; 41(1): 53-8, 2021 Jan 12.
Artículo en Chino | MEDLINE | ID: mdl-33559443

RESUMEN

OBJECTIVE: To observe the effect of moxibustion on Nrf2/HO-1 signaling pathway in rats with diminished ovarian reserve (DOR), and to explore the protective mechanism of moxibustion on ovarian reserve function. METHODS: Forty SD rats were randomly divided into a blank group, a model group, a moxibustion group and a hormone group, 10 rats in each group. The rats in the model group, moxibustion group and hormone group were treated with intragastric administration of tripterysium glycosides turbid liquid to prepare DOR model. The rats in the blank group were treated with intragastric administration of sodium chloride solution with the same volume, once a day for 14 days. The rats in the hormone group were treated with hormone sequential therapy for 14 days from the day of modeling; the rats in the moxibustion group were treated with moxibustion at bilateral "Shenshu" (BL 23) or "Guanyuan" (CV 4) and "Zhongwan" (CV 12) from the day of modeling, and the two groups acupoints were alternated every other day, 10 min each time, for 14 consecutive days. The estrus cycle was observed every day by vaginal exfoliated cell smear, and the estrus cycle disorder rate in each group was calculated. After the intervention, the HE staining was used to observe the histological morphology of ovaries; ELISA was used to detect the contents of follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), anti Mullerian hormone (AMH), superoxide dismutase (SOD) and malondialdehyde (MDA); the protein levels of Nrf2 and HO-1 in ovarian tissue were detected by immunohistochemistry; real-time PCR (TaqMan probe method) was used to detect the expression of Nrf2 and HO-1 mRNA. RESULTS: Compared with the blank group, the rate of estrus cycle disorder in the model group was increased (P<0.01); compared with the model group, the rate of estrus cycle disorder in the moxibustion group and hormone group was decreased (P<0.01). Compared with the blank group, the serum contents of FSH, LH and MDA in the model group were increased (P<0.01), and the serum contents of E2, AMH and SOD were decreased (P<0.01). Compared with the model group, the serum contents of FSH, LH and MDA in the moxibustion group and hormone group were decreased (P<0.01, P<0.05), and the serum contents of E2, AMH and SOD were increased (P<0.01). Compared with the blank group, the protein and mRNA expression of Nrf2 and HO-1 in the model group were decreased (P<0.01); compared with the model group, the protein and mRNA expressions of Nrf2 and HO-1 in the moxibustion group and hormone group were increased (P<0.01). CONCLUSION: Moxibustion could reduce the rate of estrus cycle disorder, improve the level of serum sex hormones and antioxidant stress in DOR rats, and the mechanism may be related to the regulation of Nrf2/HO-1 signaling pathway.


Asunto(s)
Moxibustión , Reserva Ovárica , Animales , Femenino , Humanos , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal
3.
Life Sci ; 268: 119015, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33412215

RESUMEN

AIMS: Metformin improves vascular function in obese type 2 diabetic patients. 8-Oxoguanine glycosylase (OGG1) is a main DNA glycosylase that is involved in vascular complications in various diseases. However, whether metformin suppresses endothelial reactive species oxygen production via the OGG1 pathway is unclear. MAIN METHODS: Human umbilical vein endothelial cells (HUVECs) were exposed to HG (high glucose) with or without metformin. OGG1 and AMPKα levels were measured after metformin treatment, while HG-induced ROS were measured by a DHE probe. KEY FINDINGS: Metformin reduced HG-induced endothelial ROS by upregulating OGG1. Additionally, OGG1 protein expression was dependent on its mRNA stability, which was reversed by genetic inhibition of AMPKα and Lin-28. Furthermore, the effect of OGG1 on HG-induced ROS was partially dependent on the AHR/Nrf2 pathway in HUVECs. SIGNIFICANCE: These results suggested that metformin modulated HG-induced endothelial ROS via the AMPKα/Lin-28/OGG1 pathway.


Asunto(s)
ADN Glicosilasas/metabolismo , Metformina/farmacología , Proteínas de Unión al ARN/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Proteínas Quinasas Activadas por AMP/antagonistas & inhibidores , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , ADN Glicosilasas/genética , Regulación de la Expresión Génica/efectos de los fármacos , Glucosa/farmacología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fosforilación , Estabilidad del ARN , Receptores de Hidrocarburo de Aril/metabolismo
4.
Ecotoxicol Environ Saf ; 208: 111610, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33396130

RESUMEN

Hepatic oxidative stress, as one important mechanism of cadmium (Cd)-induced hepatic toxicity, could, as known, be ameliorated by vitamin E (VE). However, the underlying mechanism remains to be elucidated. To investigate whether the antioxidant vitamin E can protect against Cd-induced sub-chronic liver injury associated with oxidative stress and nuclear factor erythrocyte 2-related factor 2 (Nrf2) pathway, male Sprague-Dawley rats (nine-week-old) were randomly divided into four groups (eight rats/group), namely, control, VE (100 mg/kg VE), Cd (5 mg/kg CdCl2) and VE+Cd (100 mg/kg VE+5 mg/kg CdCl2), and received intragastric administration of Cd and/or VE for four weeks. Cd-exposure alone resulted in reduced liver weight, liver histological alteration and oxidative stress, accumulation of Cd in the liver, elevated ALT and AST concentrations in serum together with decreased mRNA and protein expressions of Nrf2 pathway related molecules (Nrf2, HO-1, NQO-1, GCLC, GCLM and GST). However, the co-treatment of Cd and VE significantly ameliorated the changes mentioned above, and promoted the expression of genes and proteins of Nrf2 pathway related molecules in comparison to the Cd-exposure alone. Our results indicate that the protective effect of VE against Cd-induced sub-chronic hepatic damage in rats is associated with the inhibition of oxidative stress and activation of Nrf2 pathway.


Asunto(s)
Antioxidantes/farmacología , Cadmio/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Contaminantes Ambientales/toxicidad , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Vitamina E/farmacología , Animales , Antioxidantes/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Pruebas de Función Hepática , Masculino , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Transducción de Señal
5.
Nat Commun ; 12(1): 16, 2021 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-33397898

RESUMEN

Autophagy contributes to the selective degradation of liquid droplets, including the P-Granule, Ape1-complex and p62/SQSTM1-body, although the molecular mechanisms and physiological relevance of selective degradation remain unclear. In this report, we describe the properties of endogenous p62-bodies, the effect of autophagosome biogenesis on these bodies, and the in vivo significance of their turnover. p62-bodies are low-liquidity gels containing ubiquitin and core autophagy-related proteins. Multiple autophagosomes form on the p62-gels, and the interaction of autophagosome-localizing Atg8-proteins with p62 directs autophagosome formation toward the p62-gel. Keap1 also reversibly translocates to the p62-gels in a p62-binding dependent fashion to activate the transcription factor Nrf2. Mice deficient for Atg8-interaction-dependent selective autophagy show that impaired turnover of p62-gels leads to Nrf2 hyperactivation in vivo. These results indicate that p62-gels are not simple substrates for autophagy but serve as platforms for both autophagosome formation and anti-oxidative stress.


Asunto(s)
Autofagosomas/metabolismo , Estrés Oxidativo , Proteína Sequestosoma-1/metabolismo , Animales , Proteínas Reguladoras de la Apoptosis/metabolismo , Autofagosomas/ultraestructura , Autofagia , Línea Celular , Geles , Hepatocitos/metabolismo , Hepatocitos/ultraestructura , Humanos , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Hígado/lesiones , Hígado/patología , Ratones Endogámicos C57BL , Proteínas Asociadas a Microtúbulos/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Unión Proteica , Liposomas Unilamelares
6.
Nat Commun ; 12(1): 174, 2021 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-33420030

RESUMEN

The immunosuppressive microenvironment that is shaped by hepatic metastatic pancreatic ductal adenocarcinoma (PDAC) is essential for tumor cell evasion of immune destruction. Neutrophils are important components of the metastatic tumor microenvironment and exhibit heterogeneity. However, the specific phenotypes, functions and regulatory mechanisms of neutrophils in PDAC liver metastases remain unknown. Here, we show that a subset of P2RX1-negative neutrophils accumulate in clinical and murine PDAC liver metastases. RNA sequencing of murine PDAC liver metastasis-infiltrated neutrophils show that P2RX1-deficient neutrophils express increased levels of immunosuppressive molecules, including PD-L1, and have enhanced mitochondrial metabolism. Mechanistically, the transcription factor Nrf2 is upregulated in P2RX1-deficient neutrophils and associated with PD-L1 expression and metabolic reprogramming. An anti-PD-1 neutralizing antibody is sufficient to compromise the immunosuppressive effects of P2RX1-deficient neutrophils on OVA-activated OT1 CD8+ T cells. Therefore, our study uncovers a mechanism by which metastatic PDAC tumors evade antitumor immunity by accumulating a subset of immunosuppressive P2RX1-negative neutrophils.


Asunto(s)
Inmunosupresores/farmacología , Neoplasias Hepáticas/inmunología , Neutrófilos/metabolismo , Neoplasias Pancreáticas/inmunología , Microambiente Tumoral/inmunología , Animales , Antígeno B7-H1/metabolismo , Linfocitos T CD8-positivos/inmunología , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/patología , Modelos Animales de Enfermedad , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Noqueados , Mitocondrias/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Páncreas/inmunología , Páncreas/patología , Neoplasias Pancreáticas/patología , Receptores Purinérgicos P2X/genética , Receptores Purinérgicos P2X/inmunología , Receptores Purinérgicos P2X/metabolismo
7.
Aquat Toxicol ; 231: 105739, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33434705

RESUMEN

Cadmium (Cd) with no known functional role in any life-form has myriad of harmful effects. The present study was designed to elucidate the mechanism of Cd-induced oxystress generation and its impact on antioxidant and apoptosis signaling pathways in head kidney macrophage (HKM) of Channa punctatus Bloch. Fish were sampled and acclimatized with one group treated with cadmium chloride (CdCl2) (1.96 mg/L) and another as untreated control group, both kept under observation for 7 days. Exposure to Cd caused ultrastructural changes along with reduced head kidney somatic index (HKSI). Significantly increased levels of reactive oxygen species (ROS), respiratory burst activity, lipid peroxidation, DNA fragmentation and superoxide dismutase were found in the HKM from the treated group as compared to control. In contrast, antioxidant enzymes like catalase and reduced glutathione activity decreased in the Cd exposed group. The suppressed antioxidant activity was further confirmed and corroborated from the altered expression of Kelch-like ECH-associated protein 1 (Keap1) and nuclear factor erythroid 2-related factor 2 (Nrf2) genes, the major player of antioxidant pathway. Cd induced alteration in Nrf2-Keap1 signaling pathway was also validated by the diminished levels of Nrf2 dependent expression of protein like heme oxygenase-1 (HO-1). The flow cytometry analysis supported the event of apoptosis in Cd exposed group as compared to control, which was further confirmed by the upregulated expression of caspase-3, caspase-8, caspase-9, TNF-α and p53 genes from the real-time gene expression study. In addition, altered protein level of cytochrome C validates the incidence of apoptosis. Altogether, our results demonstrate that exposure to Cd caused oxidative stress in HKM of Channa punctatus Bloch. by compromising the antioxidant enzyme activities via the down regulation of expression of genes related to antioxidant signaling pathway besides encouraging apoptosis via both mitochondrial and death receptor pathway.


Asunto(s)
Apoptosis , Cadmio/toxicidad , Peces/metabolismo , Riñón Cefálico/citología , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Macrófagos/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Animales , Antioxidantes/metabolismo , Apoptosis/efectos de los fármacos , Catalasa/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/ultraestructura , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Receptores de Muerte Celular/metabolismo , Transducción de Señal/efectos de los fármacos , Superóxido Dismutasa/metabolismo , Contaminantes Químicos del Agua/toxicidad
8.
J Ethnopharmacol ; 265: 113271, 2021 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-32853742

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Cyclophosphamide (CTX) is a first line chemotherapeutic agent, but often limited for its unstable therapeutic effect and serious side effects. Ginsenosides could facilitate the anti-tumor efficiency of CTX, including benefiting therapeutic effect and decreasing side effects. AIM OF THE STUDY: To investigate the potential mechanism of ginsenosides on benefiting the anti-tumor efficiency of CTX. MATERIALS AND METHODS: Mammary carcinoma mice were applied to investigate the anti-tumor efficiency and potential mechanism of combinational treatment of ginsenosides and CTX. Therapeutic effect was evaluated based on survival rate, tumor burden, tumor growth inhibition rate, and apoptosis and histological changes of tumor tissues. Anti-tumor immunity was studied by measuring serum level of anti-tumor cytokines. Gut mucositis, one of lethal side effects of CTX, was evaluated by diarrhea degree, gut permeability and tight junction proteins expressions. Gut microbial diversity was analyzed by 16S rRNA gene sequencing, and fecal transplant and antibiotics sterilized animals were performed to evaluate the therapeutic effect of gut microbiota on tumor suppression. RESULTS: Ginsenosides facilitated the therapeutic effect of CTX in mice, which manifested as prolonged survival rate, decreased tumor burden, as well as enhanced tumor growth inhibition rate and apoptosis. The favoring effect was related to elevation of anti-tumor immunity which manifested as the increased anti-tumor cytokines (INF-γ, IL-17, IL-2 and IL-6). Further studies indicated the elevation was ascribed to ginsenosides promoted reproduction of gut probiotics including Akkermansia, Bifidobacterium and Lactobacillus. Moreover, co-administration of ginsenosides in mice alleviated CTX-induced gut mucositis, including lower gut permeability, less diarrhea, less epithelium damage and higher tight junction proteins. Further researches suggested the alleviation was related to ginsenosides activated Nrf2 and inhibited NFκB pathways. CONCLUSION: Ginsenosides show dual roles to facilitate the anti-tumor efficiency of CTX, namely promote the anti-tumor immunity through maintaining gut microflora and ameliorate gut mucositis by modulating Nrf2 and NFκB pathways.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Ciclofosfamida/farmacología , Ginsenósidos/farmacología , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Apoptosis/efectos de los fármacos , Ciclofosfamida/administración & dosificación , Citocinas/sangre , Femenino , Microbioma Gastrointestinal/efectos de los fármacos , Ginsenósidos/administración & dosificación , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos ICR , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , ARN Ribosómico 16S , Tasa de Supervivencia
9.
Biomed Pharmacother ; 134: 111130, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33348309

RESUMEN

OBJECTIVE: Dimethyl fumarate (DMFU), a known Nrf2 activator, has proven its positive effect in different organs against ischemia/reperfusion (Is/Re) injury. Nevertheless, its possible impact to modulate intestinal Is/Re-induced injury has not been previously demonstrated before. Hence, this study aimed to investigate DMFU mechanistic maneuver against intestinal Is/Re. METHODS: To accomplish this goal, Wistar rats were allocated into four groups; Sham-operated (SOP), intestinal Is/Re (1 h/6 h), and 14 days pre-treated DMFU (15 and 25 mg/kg/day, p.o). RESULTS: The mechanistic maneuver divulged that DMFU safeguarded the intestine partly via amplifying the expression/content of Nrf2 along with enhancing its downstream, HO-1 expression/content. In addition, DMFU lessened GSK-3ß expression/content accompanied by enriching ß-catenin expression/content. The antioxidant action was affirmed by enhancing total antioxidant capacity, besides reducing MDA, iNOS, and its by-product, NOx. The DMFU action entailed anti-inflammatory character manifested by down-regulation of expression/content NF-κB with subsequent rebating the contents of TNF-α, IL-1ß, and P-selectin, as well as MPO activity. Moreover, DMFU had anti-apoptotic nature demonstrated through enriching Bcl-2 level and diminishing that of caspase-3. CONCLUSION: DMFU purveyed tenable novel protective mechanisms and mitigated events associated with intestinal Is/Re mischief either in the lower or the high dose partly by amending of oxidative stress and inflammation through the modulation of Nrf2/HO-1, GSK-3ß, and Wnt/ß-catenin pathways.


Asunto(s)
Antiinflamatorios/farmacología , Dimetilfumarato/farmacología , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Hemo Oxigenasa (Desciclizante)/metabolismo , Enfermedades Intestinales/prevención & control , Intestinos/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Daño por Reperfusión/prevención & control , Vía de Señalización Wnt/efectos de los fármacos , Animales , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Modelos Animales de Enfermedad , Glucógeno Sintasa Quinasa 3 beta/genética , Hemo Oxigenasa (Desciclizante)/genética , Enfermedades Intestinales/enzimología , Enfermedades Intestinales/genética , Enfermedades Intestinales/patología , Intestinos/enzimología , Intestinos/patología , Masculino , Factor 2 Relacionado con NF-E2/genética , Estrés Nitrosativo/efectos de los fármacos , Ratas Wistar , Daño por Reperfusión/enzimología , Daño por Reperfusión/genética , Daño por Reperfusión/patología
10.
Food Chem ; 337: 127921, 2021 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-32919266

RESUMEN

Antioxidant peptides obtained from snakehead (Channa argus) soup (SHS) after simulated gastrointestinal (GI) digestion were separated, identified and characterized. Results showed that the fraction with MW < 3 kDa had the highest antioxidant capacity. Four novel antioxidant peptides were identified after RP-HPLC and UPLC-MS/MS. PGMLGGSPPGLLGGSPP and SDGSNIHFPN had the highest DPPH radical scavenging activity (IC50 = 1.39 mM) and Fe2+ chelating ability (IC50 = 4.60 mM), respectively. Structures in silico for IVLPDEGK, PGMLGGSPPGLLGGSPP and SDGSNIHFPN suggest at least one ß-turn and/or α-helix, which are associated with antioxidant activity. Moreover, our results showed that these three peptides docked with a recombinant Kelch-like ECH-associated protein 1 (Keap1) with a binding score greater than TX6, a good ligand of Keap1. The cell viability assay also showed significant cytoprotective effects against H2O2-induced cellular oxidative damage. This information implies that antioxidant mechanisms of novel SHS peptides occurred via activation of cellular anti-oxidation Keap1-Nrf2 signaling pathway.


Asunto(s)
Peces/metabolismo , Péptidos/aislamiento & purificación , Animales , Antioxidantes/química , Antioxidantes/aislamiento & purificación , Cromatografía Líquida de Alta Presión , Digestión , Humanos , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Péptidos/química , Espectrometría de Masas en Tándem
11.
Food Chem ; 340: 127931, 2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-32871358

RESUMEN

Thinned peach is abundant in polyphenols, and has been shown to exhibit various bioactivities. In this study, we evaluated the underlying immunomodulatory activity of polyphenol extracts of thinned peach (PETP) via the NF-κB and Nrf2 signaling pathways in RAW264.7 macrophages. The results demonstrated that the PETP efficiently activated the nuclear translocation of NF-κB and Nrf2, as well as downstream cytokines (IL-1ß, IL-6, TNF-α and IFN-γ), SOD activity and ROS levels in RAW264.7 cells. Specifically, the PETP of natural drying and hot air drying exhibited less efficacy than that of freeze drying in NF-κB pathway. Interestingly, the PETP of hot air drying at 50 °C was more effective than freeze-dried PETP in activating Nrf2 nuclear translocation. Additionally, 50 µg/mL PETP enhanced immune responses, whereas 800 µg/mL PETP inhibited inflammatory development in macrophages. These findings indicated that different PETP affected the immunomodulation effects differently, which associated with the drying methods and incubation concentrations.


Asunto(s)
Desecación/métodos , Factores Inmunológicos/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Polifenoles/farmacología , Prunus persica/química , Animales , Citocinas/metabolismo , Liofilización , Factores Inmunológicos/química , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Polifenoles/química , Células RAW 264.7 , Transducción de Señal/efectos de los fármacos
12.
Ecotoxicol Environ Saf ; 207: 111231, 2021 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-32916527

RESUMEN

Lead, a common metallic contaminant, is widespread in the living environment, and has deleterious effects on the reproductive systems of humans and animals. Although numerous toxic effects of lead have been reported, the effects and underlying mechanisms of the impacts of lead exposure on the female reproductive system, especially oocyte maturation and fertility, remain unknown. In this study, mice were treated by gavage for seven days to evaluate the reproductive damage and role of Nrf2-mediated defense responses during lead exposure. Lead exposure significantly reduced the maturation and fertilization of oocytes in vivo. Additionally, lead exposure triggered oxidative stress with a decreased glutathione level, increased amount of reactive oxygen species, and abnormal mitochondrial distribution. Moreover, lead exposure caused histopathological and ultrastructural changes in oocytes and ovaries, along with decreases in the activities of catalase, glutathione peroxidase, total superoxide dismutase, and glutathione-S transferase, and increases in the levels of malonaldehyde in mouse ovaries. Further experiments demonstrated that lead exposure activated the Nrf2 signaling pathway to protect oocytes against oxidative stress by enhancing the transcription levels of antioxidant enzymes. In conclusion, our study demonstrates that lead activates the Nrf2/Keap1 pathway and impairs oocyte maturation and fertilization by inducing oxidative stress, leading to a decrease in the fertility of female mice.


Asunto(s)
Sustancias Peligrosas/toxicidad , Plomo/toxicidad , Animales , Antioxidantes/metabolismo , Catalasa/metabolismo , Femenino , Glutatión Peroxidasa/metabolismo , Humanos , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Plomo/metabolismo , Malondialdehído/metabolismo , Ratones , Factor 2 Relacionado con NF-E2/metabolismo , Oocitos/efectos de los fármacos , Oogénesis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Superóxido Dismutasa/metabolismo
13.
Ecotoxicol Environ Saf ; 207: 111320, 2021 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-32947215

RESUMEN

Mercury (Hg) is a hazardous metal, poses environmental problems with severe human health effects; whereas zinc (Zn) is an essential micronutrient with antioxidant properties. The purpose of this research was to investigate the effect of Zn on inorganic Hg-induced cytotoxicity in the PC12 cells. The cells were treated with HgCl2 (5 µM) for 48 h with/without 1 h prior ZnCl2-treatment (100 µM) and deliberated for further analysis. After 48 h of incubation with only Hg2+, the cell showed reduced cell viability, compromised cell membrane, DNA degradation, depleted glutathione level, ROS generation and drastically increased apoptosis. Subsequently, Hg2+-treated cells demonstrated a significant downregulation of akt, mTOR, ERK1, Nrf2, HO1, Bcl-2, Bcl-xL, and upregulation of p53, Bax, cytochrome c and cleaved caspase 3, indicating intrinsic apoptosis induction. However, cells pretreated with Zn2+ before Hg2+-exposure showed a significant improvement in cell viability, cell membrane, DNA damage, glutathione level, ROS amount and apoptotic cells, with a significant upregulation in mTOR, akt, ERK1, Nrf2, HO1, Bcl-2 and Bcl-xL, and downregulation in p53, Bax, cytochrome c and cleaved caspase 3, indicating inhibition of apoptosis. The findings suggested that Zn2+-pretreatment not only improves glutathione content but also induces activation of Nrf2-HO1 pathway, which would tend to suppress Hg-cytotoxicity.


Asunto(s)
Glutatión/metabolismo , Mercurio/toxicidad , Factor 2 Relacionado con NF-E2/metabolismo , Zinc/metabolismo , Animales , Antioxidantes/metabolismo , Apoptosis/efectos de los fármacos , Caspasa 3 , Supervivencia Celular/efectos de los fármacos , Humanos , Células PC12 , Proteínas Proto-Oncogénicas c-bcl-2 , Ratas , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos
14.
Phytomedicine ; 80: 153370, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33113504

RESUMEN

BACKGROUND: Cisplatin (DDP) is the first-in-class drug for advanced and non-targetable non-small-cell lung cancer (NSCLC). A recent study indicated that DDP could slightly induce non-apoptotic cell death ferroptosis, and the cytotoxicity was promoted by ferroptosis inducer. The agents enhancing the ferroptosis may therefore increase the anticancer effect of DDP. Several lines of evidence supporting the use of phytochemicals in NSCLC therapy. Ginkgetin, a bioflavonoid derived from Ginkgo biloba leaves, showed anticancer effects on NSCLC by triggering autophagy. Ferroptosis can be triggered by autophagy, which regulates redox homeostasis. Thus, we aimed to elucidate the possible role of ferroptosis involved in the synergistic effect of ginkgetin and DDP in cancer therapy. METHODS: The promotion of DDP-induced anticancer effects by ginkgetin was examined via a cytotoxicity assay and western blot. Ferroptosis triggered by ginkgetin in DDP-treated NSCLC was observed via a lipid peroxidation assay, a labile iron pool assay, western blot, and qPCR. With ferroptosis blocking, the contribution of ferroptosis to ginkgetin + DDP-induced cytotoxicity, the Nrf2/HO-1 axis, and apoptosis were determined via a luciferase assay, immunostaining, chromatin immunoprecipitation (CHIP), and flow cytometry. The role of ferroptosis in ginkgetin + DDP-treated NSCLC cells was illustrated by the application of ferroptosis inhibitors, which was further demonstrated in a xenograft nude mouse model. RESULTS: Ginkgetin synergized with DDP to increase cytotoxicity in NSCLC cells, which was concomitant with increased labile iron pool and lipid peroxidation. Both these processes were key characteristics of ferroptosis. The induction of ferroptosis mediated by ginkgetin was further confirmed by the decreased expression of SLC7A11 and GPX4, and a decreased GSH/GSSG ratio. Simultaneously, ginkgetin disrupted redox hemostasis in DDP-treated cells, as demonstrated by the enhanced ROS formation and inactivation of the Nrf2/HO-1 axis. Ginkgetin also enhanced DDP-induced mitochondrial membrane potential (MMP) loss and apoptosis in cultured NSCLC cells. Furthermore, blocking ferroptosis reversed the ginkgetin-induced inactivation of Nrf2/HO-1 as well as the elevation of ROS formation, MMP loss, and apoptosis in DDP-treated NSCLC cells. CONCLUSION: This study is the first to report that ginkgetin derived from Ginkgo biloba leaves promotes DDP-induced anticancer effects, which can be due to the induction of ferroptosis.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Biflavonoides/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Hemo-Oxigenasa 1/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Factor 2 Relacionado con NF-E2/metabolismo , Células A549 , Animales , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Biflavonoides/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Cisplatino/administración & dosificación , Receptores ErbB/genética , Ferroptosis/efectos de los fármacos , Ginkgo biloba/química , Hemo-Oxigenasa 1/genética , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones Desnudos , Hojas de la Planta/química , Ensayos Antitumor por Modelo de Xenoinjerto
15.
Life Sci ; 266: 118905, 2021 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-33333051

RESUMEN

AIMS: Ferroptosis is involved in the pathogenesis of spinal cord injury (SCI). Carnosic acid (CA) is a natural phenolic diterpene, which possesses diversiform activities. However, whether the protective effect of CA on SCI is partly due to inhibition of ferroptosis was seldom investigated. Therefore, the objective of this study aimed to investigate the role of CA on ferroptosis in PC12 cells and the underlying mechanisms. MAIN METHODS: Cell viability, malondialdehyde (MDA) contents, glutathione (GSH) levels, and iron levels were detected to identify the construction of ferroptosis model in PC12 cell induced by erastin. The safe concentrations of CA on PC12 cells were measured via cell counting kit-8 (CCK-8) assays. Then, cellular MDA contents, GSH levels, iron levels, reactive species (RS) generation, and mitochondrial morphology were tested to determine the influence of CA on ferroptosis in erastin-treated PC12 cells. In addition, Western blot and RT-qPCR were utilized to detecteddetect the ferroptosis-related genes and proteins expression levels. KEY FINDINGS: Our study indicated that treatment with CA could reversed the increased MDA, iron, and RS levels, as well as the decreased GSH levels in erastin-treated PC12 cells. The protective effect of CA could be blocked by ML385. The inhibitory effect of CA on ferroptosis probably was partially governed by activation of Nrf2 to regulate the GSH synthesis and metabolism and cellular iron homeostasis. SIGNIFICANCE: CA can inhibit ferroptosis in PC12 cells induced by erastin via activating Nrf2 pathway, indicating that CA could lead to neuroprotective effect by restraining the occurrence of ferroptosis.


Asunto(s)
Abietanos/farmacología , Ferroptosis , Glutatión/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Sustancias Protectoras/farmacología , Especies Reactivas de Oxígeno/metabolismo , Animales , Antioxidantes/farmacología , Apoptosis , Peroxidación de Lípido , Factor 2 Relacionado con NF-E2/genética , Células PC12 , Ratas , Transducción de Señal
16.
Phytomedicine ; 80: 153388, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33113501

RESUMEN

BACKGROUND: Insulin resistance (IR) and lipotoxicity were evidenced as the major nonalcoholic steatohepatitis (NASH) initiators. However, absence of the effective treatment against NASH progression raised our aim to discover a new promising insulin modulator and NSH preventer. PURPOSE: Our study aimed to extract and prepare a nitriles rich fraction (NRF) from Diceratella elliptica (DC.) Jonsell, investigate its insulin-sensitizing & anti-NASH potentialities and address its molecular targets in IR-NASH pathogenesis. STUDY DESIGN: NRF was prepared using natural autolysis method and compounds were identified. Then, seventy male Wistar rats were feed high fat diet (HFD) or normal pellets for 35 days. In day 14th, HFD rats were injected by Streptozotocin (STZ) once and treatment was started in day 21st with either NRF (30, 60 and 120 mg/kg; orally) or pioglitazone (PioG) (10 mg/kg; i.p) beside HFD. While, NRF-alone rats were treated with NRF (120 mg/kg; orally) beside the normal pellets. Body weight, glucose homeostasis, hepatopathological examinations were performed. METHODS: Gas liquid chromatography-mass spectrophotometry (GLC/MS) was used for compounds' identification while spectrophotometer was used for total glucosinolates (GLS) quantification. Also, the biochemical and molecular investigations concerned with liver lipotoxicity, oxidative stress, inflammation and insulin signaling pathway were investigated and confirmed with the computational prediction of the major compounds' targets. RESULTS: Butenyl and benzyl GLS were the major along with other volatile compounds. NRF had significantly increased the insulin sensitivity and improved NASH-hisptopathology showing hepatoprotective effect. While, the fraction's anti-NASH potentiality was evidenced in the normalized hepatic steatosis markers, inflammation and oxidative stress key transcriptional factors resulting in induction of insulin receptor substrates (IRSs) phosphorylation and its downstream effectors. CONCLUSION: NRF has reversed IR, stimulated leptin secretion and prevented NASH initiation showing promising anti-NASH and anti-fibrotic effects.


Asunto(s)
Brassicaceae/química , Resistencia a la Insulina , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Extractos Vegetales/farmacología , Animales , Dieta Alta en Grasa/efectos adversos , Glucosinolatos/análisis , Leptina/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/antagonistas & inhibidores , FN-kappa B/metabolismo , Nitrilos/química , Nitrilos/farmacología , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Pioglitazona/farmacología , Extractos Vegetales/química , Ratas Wistar , Transducción de Señal
17.
Phytomedicine ; 81: 153411, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33310307

RESUMEN

BACKGROUND: Nodakenin, a coumarin glucoside isolated from the roots of Angelica biserrata, has been reported to have anti-inflammatory, antibacterial, anticancer effects. However, despite these studies, the potential liver protective effects of nodakenin in inflammatory liver injury models have not been reported. METHODS: A mouse model of inflammatory liver injury was induced by injection of lipopolysaccharide (LPS) (15 mg/kg, intraperitoneally (i.p)). Liver tissue AST, ALT, ROS, T-GSH and T-SOD were analyzed by ELISA. The concentrations of TNF-α, IL-6, and IL-1ß in serum of LPS-induced inflammatory liver injury mice were analyzed. The mRNA expression levels of GPx1, catalase, SOD1, SOD2, TNF-α, IL-6, IL-1ß, iNOS and COX-2 were analyzed using real-time PCR. The expressions of MAPK, IRF3, NF-κB, Nrf2, HO-1, caspase-3 and caspase-7 were analyzed using western blotting. Liver tissue was stained with IHC to confirm NF-κB, Nrf-2, HO-1, caspase-3, Bax, and Bcl2. Tunnel analysis was performed to confirm the fragmented nuclear DNA characteristics of apoptosis. RESULTS: The administration of nodakenin (10 and 30 mg/kg) reduced serum aminotransferase levels compared to LPS-induced liver damage and significantly improved the oxidative state of liver tissue and pathological damage. Moreover, inhibited the phosphorylation of transforming growth factor beta (TGF-ß)-activated kinase (TAK)-1 in LPS-induced inflammatory liver injury model, and significantly inhibited the transcriptional of nuclear factor-kappa B (NF-kB) and the secretion of pro-inflammatory mediators. In addition nodakenin pre-treatment also attenuated hepatocyte death by regulating apoptosis-related mitochondrial proteins, such as cysteinyl aspartate specific proteinase 3 (caspase 3), poly (ADP-ribose) polymerase (PARP), B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X (Bax). CONCLUSION: Our findings suggest that nodakenin has anti-inflammatory, anti-oxidant and anti-apoptotic activity and may be an adjunctive prevention agent for liver injury.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Cumarinas/farmacología , Glucósidos/farmacología , Hepatitis Animal/tratamiento farmacológico , Lipopolisacáridos/toxicidad , Animales , Antiinflamatorios no Esteroideos/farmacología , Antioxidantes/metabolismo , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Citocinas/sangre , Citocinas/genética , Enzimas/metabolismo , Hepatitis Animal/metabolismo , Hepatitis Animal/patología , Masculino , Ratones Endogámicos ICR , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/farmacología
18.
J Ethnopharmacol ; 266: 113444, 2021 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-33027641

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Acorn obtained from the Quercus liaotungensis Koidz tree is consumed as a Chinese folk medicine for the treatment of diarrhea, abdominal pain, and inflammation, also having strong antioxidant activity and have been utilized for the treatment of diabetes in China. However, its mechanism of action on complications of diabetes and oxidative stress is unclear. AIM OF THE STUDY: The purpose of this research was to assess the effects of acorn (Quercus liaotungensis Koidz) ethanol extract (AE) on pancreatic ß-cell dysfunction through a streptozotocin (STZ)-damaged mouse normal pancreatic ß-cell (MIN6 cell) model in vitro, and by using a high-fat and high-sugar diet with STZ-induced diabetic rat model in vivo to explore the possible mechanism of action against diabetes. MATERIALS AND METHODS: MIN6 cells were pretreated with AE (20, 40, 80 µM) for 2 h and then treated with 3 mM STZ for 24 h. Cell viability was measured by MTT assay. The amount of intracellular reactive oxygen species was measured by 2,7-dichlorodi-hydrofluorescein diacetate. The activities of insulin secretion, superoxide dismutase, catalase and glutathione were determined by kits. Sprague Dawley rats were either given normal feed or a high sugar and fat diet for four weeks, followed STZ (25 mg/kg, via i. p.) was given. Rats with fasting blood glucose ≥11.1 mmol/l after one week were deemed to be diabetic. Animals were divided into 5 groups, which received saline (10 mL/kg), metformin (200 mg/kg), or AE at doses of 200 and 400 mg/kg during 4 weeks by oral gavage. Blood samples were used to evaluate hematological and biochemical indicators, and pancreas was removed for post-analysis. Body weight and fasting blood glucose were recorded weekly. The expression levels of Bax, Bcl-2, p38, p-p38, Nrf2 and HO-1 were determined by Western blot. RESULTS: Data showed that AE inhibited apoptosis and increased antioxidant level in STZ-induced MIN6 cells. In addition, the AE-administered group lowered blood glucose, increased insulin secretion, and alleviated weight loss in the diabetic rats. Histopathologically, the AE-administered group reduced pancreatic injury by significantly restoring the insulin content in ß-islets. It was observed that the anti-diabetic effects of AE were associated with the suppressed the p38 MAPK pathway and actived the Nrf2 pathway. CONCLUSIONS: The ameliorative impact of AE on diabetes may be attributed to protection of the function of pancreatic ß islets and by improving serum insulin levels, hence reducing the blood glucose, which involved in the p38 MAPK and Nrf2 pathways.


Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Extractos Vegetales/farmacología , Quercus/química , Animales , Glucemia/efectos de los fármacos , Línea Celular , Relación Dosis-Respuesta a Droga , Hemo-Oxigenasa 1/metabolismo , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/aislamiento & purificación , Hipoglucemiantes/farmacología , Insulina/sangre , Masculino , Metformina/farmacología , Ratones , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/administración & dosificación , Ratas , Ratas Sprague-Dawley , Estreptozocina , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
19.
J Ethnopharmacol ; 266: 113454, 2021 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-33065254

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Adhatoda vasica Nees., which existed in a large; number of Tibetan medicine prescriptions for hepatopathy, used as an adjuvant to treat liver diseases. HYPOTHESIS/PURPOSE: Oxidative stress is the key player in the development and progression of liver pathogenesis. In recent years, research is increasingly being focused on exploitation of the active components from medicinal plants to combat the liver oxidative injury. In our study, we aimed to screen the active principles from A. vasica and clarify whether they could relieve oxidative damage induced by tert-Butyl hydroperoxide (t-BHP) and its potential mechanism via activating AMPK/p62/Nrf2 pathway. MATERIALS AND METHODS: Ultra performance liquid chromatography (UPLC) was adopted for analysis of chemical composition in the extracts. Furthermore, the antioxidant activity of the fractions was evaluated using DPPH, ABTS and reducing power assay. Along with this, the compounds in this fraction with highest antioxidant activity were analyzed using UPLC-MS. Based on this, the condition for extracting flavonoids of this subfraction was optimized via response surface method. CCK-8 assay was used to detect cell viability. Detection kits were used to measure the activity changes of AST, ALT, LDH and CAT as well as MDA and GSH levels induced by t-BHP. Detection of reactive oxygen species (ROS) production was used DCFH-DA probe. DAPI staining and flow cytometry was used to detect cell apoptosis. In terms of the mechanistic studies, the expression of proteins involved in AMPK/p62/Nrf2 pathway was measured using western blotting. RESULTS: Eventually, 70% ethanol extract from leaf of A. vasica was chosen due to its highest active components compared with other extracts. Further, ethyl acetate fraction derived from 70% ethanol extract in A. vasica (AVEA) possess highest ability for scavenging DPPH and ABTS free radicals as well as strongest reducing power than other fractions. Chemical composition analysis showed that AVEA contained 17 compounds, including 1 quinazoline alkaloid, 12 flavonoid-C-glycosides and 4 flavonoid-O-glycosides. In addition, the conditions (ratio of solid-liquid 1:14, the concentration of ethanol 73%, and the temperature 65 °C) were selected to enrich the flavonoids in AVEA. Furthermore, AVEA could attenuate t-BHP induced hepatocyte damage via increasing the cell viability, restoring abnormal the activities of AST, ALT, LDH and CAT as well as the levels of MDA and GSH. ROS fluorescence intensity was reduced by AVEA. Meanwhile, it could inhibit the cell apoptosis of BRL 3 A cells, as evidenced by restoration of cell morphology and decreasing the number of apoptotic cells. Further mechanistic studies indicated AVEA could promote p-AMPK expression to further induce autophagy adaptor-p62 protein expression, which could autophagic degradation of Keap1, leading to Nrf2 release and translocation into nucleus to induce antioxidant genes (HO-1, NQO-1, GCLC and GCLM) expression. CONCLUSION: In our study, AVEA was first to screen as the active fraction in A. vasica with alkaloids and abundant flavones. Moreover, the fraction potentiates its beneficial aspect by displaying the protective role on relieving t-BHP induced oxidative stress and activating AMPK/p62/Nrf2 pathway. AVEA helps maintain the redox homeostasis of hepatic cells and could be considered as an effective candidate against oxidative stress related liver disorders.


Asunto(s)
Justicia/química , Hepatopatías/prevención & control , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Antioxidantes/aislamiento & purificación , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Células Cultivadas , Factor 2 Relacionado con NF-E2/metabolismo , Fitoquímicos/aislamiento & purificación , Fitoquímicos/farmacología , Ratas , Ratas Endogámicas BUF , Especies Reactivas de Oxígeno/metabolismo , terc-Butilhidroperóxido
20.
J Ethnopharmacol ; 266: 113474, 2021 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-33068650

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Ginkgo biloba extract (GbE) is derived from a medicinal plant and suggested as a treatment for diabetic nephropathy (DN), but the mechanism was not clarified. AIM OF STUDY: The present study investigated whether GbE prevented DN via activation of heme oxygenase (HO)-1. MATERIALS AND METHODS: Streptozotocin-induced diabetic mice were fed a high-fat diet to generate DN. Human and murine podocytes were used for the in vitro study. RESULTS: GbE improved renal function via decreasing glomerular hypertrophy, the kidney/body weight ratio, and albuminuria in DN mice. GbE reversed the reduction of synaptopodin and nephrin and enhanced HO-1 expression in the kidneys of DN mice. GbE decreased the enhancement of TNF-α, IL-6, fibronectin, and lipid accumulation in the glomeruli of DN mice. GbE attenuated the uptake of oxidized low-density lipoprotein and reduced the production of ROS in high glucose-stimulated podocytes, and HO-1 inhibitor treatment abrogated the protective effects of GbE. Nuclear factor erythroid 2-related factor 2 (Nrf-2) siRNA significantly abolished the beneficial effects of GbE via decreased HO-1 expression and enhanced TNF-α and IL-6 levels. CONCLUSIONS: GbE protected podocytes against hyperglycemia and prevented the development of DN via Nrf-2/HO-1 activation. Our findings provide further mechanistic insight into the potential use of GbE in clinical DN.


Asunto(s)
Antiinflamatorios/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Nefropatías Diabéticas/prevención & control , Extractos Vegetales/farmacología , Animales , Células Cultivadas , Diabetes Mellitus Experimental/complicaciones , Dieta Alta en Grasa , Hemo-Oxigenasa 1/metabolismo , Humanos , Hiperglucemia/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos DBA , Factor 2 Relacionado con NF-E2/metabolismo , Podocitos/efectos de los fármacos , Podocitos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Estreptozocina
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