Fucoxanthin regulates Nrf2/Keap1 signaling to alleviate myocardial hypertrophy in diabetic rats / 南方医科大学学报

OBJECTIVE@#To investigate the protective effect of fucoxanthin (FX) against diabetic cardiomyopathy and explore the underlying mechanism.@*METHODS@#Rat models of diabetes mellitus (DM) induced by intraperitoneal injection of streptozotocin (60 mg/kg) were randomized into DM model group, fucoxanthin treatment (DM+FX) group and metformin treatment (DM+ Met) group, and normal rats with normal feeding served as the control group. In the two treatment groups, fucoxanthin and metformin were administered after modeling by gavage at the daily dose of 200 mg/kg and 230 mg/kg, respectively for 12 weeks, and the rats in the DM model group were given saline only. HE staining was used to examine the area of cardiac myocyte hypertrophy in each group. The expression levels of fibrotic proteins TGF-β1 and FN proteins in rat hearts were detected with Western blotting. In the cell experiment, the effect of 1 μmol/L FX on H9C2 cell hypertrophy induced by exposure to high glucose (HG, 45 mmol/L) was evaluated using FITC-labeled phalloidin. The mRNA expression levels of the hypertrophic factors ANP, BNP and β-MHC in H9C2 cells were detected using qRT-PCR. The protein expressions of Nrf2, Keap1, HO-1 and SOD1 proteins in rat heart tissues and H9C2 cells were determined using Western blotting. The DCFH-DA probe was used to detect the intracellular production of reactive oxygen species (ROS).@*RESULTS@#In the diabetic rats, fucoxanthin treatment obviously alleviated cardiomyocyte hypertrophy and myocardial fibrosis, increased the protein expressions of Nrf2 and HO-1, and decreased the protein expressions of Keap1 in the heart tissue (P < 0.05). In H9C2 cells with HG exposure, fucoxanthin significantly inhibited the enlargement of cell surface area, lowered the mRNA expression levels of ANP, BNP and β-MHC (P < 0.05), promoted Nrf2 translocation from the cytoplasm to the nucleus, and up-regulated the protein expressions its downstream targets SOD1 and HO-1 (P < 0.05) to enhance cellular antioxidant capacity and reduce intracellular ROS production.@*CONCLUSION@#Fucoxanthin possesses strong inhibitory activities against diabetic cardiomyocyte hypertrophy and myocardial fibrosis and is capable of up-regulating Nrf2 signaling to promote the expression of its downstream antioxidant proteins SOD1 and HO-1 to reduce the level of ROS.

Protective effects of the total glycosides of Cistanche deserticola Y. C. Ma in alcoholic liver injury in mice / 药学学报

Modern pharmacological studies have shown that Cistanche deserticola (C. deserticola) has a protective effect on the liver, but its active fraction and mechanism are not clear. In order to identify the effective fraction of C. deserticola Y. C. Ma, an acute alcoholic liver injury model in mice was established with 56-proof Erguotou and different fractional extracts of C. deserticola Y. C. Ma (total glycosides, polysaccharides, and oligosaccharides) were administered. After 14 days of oral administration, liver pathology and lipid deposition were measured and the expression of nuclear factor E2-related factor (Nrf-2), kelch-like ECH-associated protein-1 (Keap-1), and plasmalemma vesicle-associated protein-1 (PV1) were measured by immunofluorescence. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), endotoxin (ET), diamine oxidase (DAO), and D-lactic acid (D-LA) in serum, and superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and malondialdehyde (MDA) in liver were measured by ELISA. All animal experiments were carried out with approval of the Experimental Animal Welfare Ethics Committee of the Peking University Health Science Center. The results show that the total glycosides of C. deserticola Y. C. Ma (400 mg·kg-1) could decrease liver pathology, decrease serum endotoxin, diamine oxidase, and D-lactic acid, and reduce hepatic lipid deposition. Total glycosides also promoted Nrf-2 transfer into the nucleus and decreased the expression of Keap-1 and PV1. In summary, the total glycosides of C. deserticola Y. C. Ma had a protective effect in acute alcoholic liver injury and the mechanism may be related to the activation of the Nrf-2/Keap-1 pathway, improvement of intestinal wall integrity, and inhibition of the transport of harmful substances into the liver.

Study on the protective effect of quercetin on age-related macular degeneration in mice based on Nrf2/Keap1/ARE pathway / 国际眼科杂志(Guoji Yanke Zazhi)

@#AIM: To investigate the protective effect and mechanism of quercetin on age-related macular degeneration in mice through Nrf2/Keap1/ARE pathway. <p>METHODS: Kunming mice were used as research objects, which were divided into control group, model group and quercetin group. Fundus examination was showed whether yellow-white like glassy sputum substances appeared in the fundus of each group of mice; OCT was used to examine the retinal thickness of each group of mice; HE staining was used to observe the changes of retinal morphology in each group of mice; FFA was observed the fundus vascular integrity of each group of mice. The activities of SOD, GSH-Px, CAT and the contents of ROS and MDA in serum were detected by ELISA; Western blot was used to detect the expression of Nrf2/Keap1/ARE related proteins in the retina of each group. <p>RESULTS: Quercetin can reduce the yellow and white glassy wart substance in the fundus of mice and increase the thickness of the retina(<i>P</i><0.05), and the points of retinal vascular leakage is significantly reduced. Compared with the model group, the a-wave amplitude and b-wave amplitude of the quercetin group were significantly higher than those of the model group(<i>P</i><0.01); Quercetin can make the retinal structure of mice clearer, necrosis and shed part of the outer nuclear layer, and reduce the content of ROS and MDA in mouse serum(all <i>P</i><0.05), and increase the activities of SOD, GSH-Px, and CAT(all <i>P</i><0.05). Compared with the model group, the expression of Nrf2 protein in the retinal cytoplasm of mice in the quercetin group was up-regulated(<i>P</i><0.05), and the expression of Nrf2 protein in the nucleus was down-regulated(<i>P</i><0.05), GCL protein expression was down-regulated(<i>P</i><0.05).<p>CONCLUSION: Quercetin improved the oxidative stress state after retinal photodamage through the Nrf2/Keap1/ARE pathway, protected the retinal function, and protected against age-related macular degeneration.

Effects of N-acetylcysteine on oxidative stress in lung tissue of smoked rats / 中国组织工程研究

BACKGROUND: N-Acetyl-L-cysteine is a precursor of glutathione, which can directly scavenge oxygen free radicals. However, it is not entirely clear whether N-acetyl-L-cysteine can alleviate smoking-induced lung injury by reducing oxidative stress. OBJECTIVE: To investigate the effects of N-acetylcysteine on oxidative stress in lung tissue of smoked rats, and to clarify its possible mechanism of action. METHODS: Thirty male rats were randomly divided into control, smoked and smoked+N-acetylcysteine groups. The rats in the smoked and smoked+N-acetylcysteine groups were placed in the passive smoking animal exposure system, with smoking of 20 cigarettes, twice/d, 1 hour/times, for 8 consecutive weeks. The rats in the smoked+N-acetylcysteine group were given 200 mg/kg N-acetylcysteine via gavage before passive smoking daily, for 8 consecutive weeks. The control rats were fed normally for 8 consecutive weeks. The study was approved by the Laboratory Animal Ethical Committee of Shenyang Medical College in October 2018, approval No. (2018)85. RESULTS AND CONCLUSION: (1) Pathological observation showed that the pulmonary tissue was disordered, alveolar septal thickening, inflammatory cell infiltration and interstitial fibrosis in the smoking group, while the pulmonary hemorrhage, the number of inflammatory cells and the degree of fibrosis in the smoking+N-acetylcysteine group were significantly reduced. (2) Compared with the control group, the expression levels of malondialdehyde-5 and inositol-alpha genes were significantly increased, and superoxide dismutase-1 gene expression was significantly decreased in the smoked group, while N-acetylcysteine could inhibit the above changes. (3) Immunofluorescence staining and western blot assay results revealed that the expression levels of malondialdehyde-5 and inositol-alpha in lung tissue of rats in the smoked+N-acetylcysteine group was significantly lower than those in the smoked group, and the expression level of superoxide dismutase-1 was significantly higher than that in the smoked group. In addition, the expression levels of Nrf2 and Keap1 mRNA and protein were significantly increased, and the expression levels of Bach1 mRNA and protein were significantly decreased in the smoking+N-acetylcysteine group. (4) These results suggest that N-acetylcysteine can protect smoking-induced lung injury by reducing oxidative stress, and which might be through activating Nrf2/Keap1 signaling pathway.

Role of Nrf2/Keap1/ARE signaling pathway in respiratory diseases / 中国药理学通报

Nrf2/Keap1/ARE is an important signaling pathway in maintaining the balance between peroxide and antioxidants. Once oxidative stress happened, Nrf2/Keap1/ARE would be ac-tivated to regulate the expression of downstream antioxidant pro-teins that could reduce the injury from oxidative stress and the level of oxidative stress. Recent researches show that Nrf2/Keap1/ARE signaling pathway is closely related to refractory re-spiratory diseases such as pulmonary fibrosis (PF), lung canc-er, chronic obstructive pulmonary disease (COPD), suggesting that Nrf2/Keap1/ARE signaling pathway may be a potential ther-apeutic target. This review focuses on the role of Nrf2/Keap1/ARE signaling pathway in refractory respiratory diseases in order to further understand the related mechanism and provide evidence for the diagnosis and treatment of refractory respiratory diseases.