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•NK relieved DSS-induced chronic colitis.•NK maintained mucosal integrity by inhibiting apoptosis.•NK regulated gut microbiota of DSS-induced chronic colitis.•NK suppressed Trp ...metabolism via inhibiting IDO-1 in DSS-induced chronic colitis.
In this study, we investigated the protective effect of Nattokinase (NK), the most active ingredient in natto used for healthcare, on dextran sulfate sodium (DSS)-induced chronic colitis and unraveled the potential mechanisms. NK dramatically attenuated clinical symptoms and pathological damage of DSS-induced chronic colitis. NK also inhibited proinflammatory cytokines production in DSS-induced colonic tissues. Mucosal integrity was maintained by NK. Moreover, nattokinase reversed DSS-induced decline of bacteria community diversity and intestinal microbial imbalance by decreasing levels of Firmicutes and increasing levels of Bacteroidetes. Tryptophan (Trp) metabolism analysis demonstrated that NK suppressed Trp catabolism especially the Kynurenine (Kyn) pathway in chronic colitis. Furthermore, NK strikingly down-regulated the protein expression of IDO-1 in chronic colitis mice. Taken together, the study demonstrated that NK relieved DSS-induced chronic colitis by regulating gut microbiota and suppressing Trp metabolism via inhibiting IDO-1. This study indicated that NK might be a promising and effective agent for IBD.
Limonin, a bioactive compound from citrus plants, exerts antioxidant activities, however its therapeutic potential in acetaminophen (APAP)-induced hepatotoxicity remains unclear.
Our study aims to ...investigate the protective effect of limonin on APAP-induced hepatotoxicity and illuminate the underlying mechanisms.
design In vitro, we chose L-02 cells to establish in vitro APAP-induced liver injury model. L-02 cells were treated with APAP (7.5 mM) for 24 h after pre-incubation with limonin (10, 25, 50 μM) or NAC (250 μM) for 2 h. In vivo, we used C57BL/6 mice as an in vivo APAP-induced liver injury model. C57BL/6 mice with pre-treatment of limonin (40, 80 mg/kg) or NAC (150 mg/kg) for 1 h, were given with a single dose of APAP (300 mg/kg).
After pre-incubation with limonin (10, 25, 50 μM) for 2 h, L-02 cells were treated with APAP (7.5 mM) for 24 h.The experiments in vitro included MTT assay, Annexin V/PI staining, measurement of reactive oxygen species (ROS), quantitative real-time PCR analysis, Western blot analysis, immunofluorescence microscopy and analysis of LDH activity. Transfection of Nrf2 or Sirt1 siRNA was also conducted in vitro. In vivo, C57BL/6 mice with pre-treatment of limonin (40, 80 mg/kg) or NAC (150 mg/kg) for 1 h, were given with a single dose of APAP (300 mg/kg). Mice were sacrificed at 4, 12 h after APAP poisoning, and analysis of ALT and AST in serum, GSH level in liver tissues, liver histological observation and immunohistochemistry were performed.
Limonin increased the cell viability and alleviated APAP-induced apoptosis in hepatocytes. Limonin also inhibited APAP-induced mitochondrial-mediated apoptosis by decreasing the ratio of Bax/Bcl-2, recovery of mitochondrial membrane potential (MMP), inhibiting ROS production and cleavage of caspase-3 in L-02 cells. Moreover, limonin induced activation of Nrf2 and increased protein expression and mRNA levels of its downstream targets, including HO-1, NQO1 and GCLC/GCLM. The inhibition of limonin on apoptosis and promotion on Nrf2 antioxidative pathway were lessened after the application of Nrf2 siRNA. In addition, limonin inhibited NF-κB transcriptional activation, NF-κB-regulated genes and protein expression of inflammatory related proteins iNOS and COX2. Furthermore, limonin increased the protein expression of Sirt1. Sirt1 siRNA transfection confirmed that limonin activated Nrf2 antioxidative pathway and inhibited NF-κB inflammatory response by upregulating Sirt1. Finally, we established APAP-induced liver injury in vivo and demonstrated that limonin alleviated APAP-induced hepatotoxicity by activating Nrf2 antioxidative signals and inhibiting NF-κB inflammatory response via upregulating Sirt1.
In summary, this study documented that limonin mitigated APAP-induced hepatotoxicity by activating Nrf2 antioxidative pathway and inhibiting NF-κB inflammatory response via upregulating Sirt1, and demonstrated that limonin had therapeutic promise in APAP-induced liver injury.
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Mitochondrial dysfunctions induced by oxidative stress could play a pivotal role in the development of testicular damage and degeneration, leading to impaired fertility in adulthood. MitoQ as ...mitochondria-targeted antioxidant has been used in many diseases for a long time, but its therapeutic effects on testicular injury ‘have not been reported yet. Here, we examined the protective action mechanism of MitoQ on testicular injury from oxidative stress induced by triptolide (TP). Mice were orally administrated with MitoQ (1.3, 2.6 and 5 .2mg/kg, respectively) in a TP-induced model of testicular damage for 14 days. And then testis injuries were comprehensively evaluated in terms of morphological changes, spermatogenesis assessment, blood-testis barrier (BTB) integrity, and apoptosis. The results demonstrated MitoQ effectively increased testicular weight, maintained the integrity of BTB, protected microstructure of testicular tissue and sperm morphology by inhibition of oxidative stress. Further mechanism studies revealed that MitoQ markedly activates the Keap1-Nrf2 antioxidative defense system characterized by increasing the expression of Nrf2 and its target genes HO-1 and NQO1. Meanwhile, MitoQ upregulated the expression of mitochondrial dynamics proteins Mfn2 and Drp-1and exerted a protective effect on mitochondria. On this basis, the results from pharmacokinetic study indicated that the MitoQ could enter into testis tissues after oral administration in despite of the low absolute bioavailability, which provided the material basis for MitoQ in the treatment of testicular damage. More importantly, MitoQ reached mitochondria quickly and had an outstanding feature of mitochondria targeting in Sertoli cells. Therefore, these results provide information for the application of MitoQ against testicular injury diseases.
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•MitoQ inhibits oxidative stress to attenuate the testis injury.•MitoQ upregulates mitochondrial dynamics protein Mfn2 and Drp-1.•MitoQ activates Nrf2/Keap1 signaling to ameliorate the oxidative stress.•MitoQ could be exposed to testis tissue by pharmacokinetic study.•MitoQ is quickly accumulated in mitochondria of sertoli cells.
Metastatic osteosarcoma usually has an unsatisfactory response to the current standard chemotherapy and causes poor prognosis. Currently, epithelial-mesenchymal transition (EMT) is reported as a ...critical event in osteosarcoma metastasis. Glaucocalyxin A, a bioactive ent-kauranoid diterpenoid, exerts anti-cancer effect on osteosarcoma by inducing apoptosis in previous study. However, the effect of Glaucocalyxin A on EMT and metastasis of osteosarcoma is unclear. In this study, we investigated the potential mechanisms of Glaucocalyxin A on EMT and metastasis of osteosarcoma. We found that Glaucocalyxin A inhibited migration and invasion of MG-63 and 143B cells. Moreover, Glaucocalyxin A increased the protein and mRNA levels of E-cadherin and decreased the protein and transcription expression of N-cadherin, Vimentin. Glaucocalyxin A also inhibited the protein and mRNA levels of EMT-associated transcription factor including Snail and Slug. Furthermore, Glaucocalyxin A inhibited transforming growth factor-β1 (TGF-β1)-induced migration, invasion and EMT of low-metastatic osteosarcoma U2OS cells. Glaucocalyxin A inhibited TGF-β-induced phosphorylation of Smad 2/3 in osteosarcoma U2OS cells. Finally, we established transplanted metastatic models of highly metastatic osteosarcoma 143B cells. Glaucocalyxin A inhibited lung metastasis in vivo. Interestingly, Glaucocalyxin A increased the protein expression of E-cadherin and reduced the protein expression of N-cadherin and Vimentin. Glaucocalyxin A inhibited the protein expression of Snail and Slug in vivo. In summary, this study demonstrated that Glaucocalyxin A inhibited EMT and TGF-β1-induced EMT by inhibiting TGF-β1/Smad2/3 signaling pathway in osteosarcoma. Therefore, Glaucocalyxin A might be a promising candidate against the metastasis of human osteosarcoma.
•Glaucocalyxin A reverses epithelial-mesenchymal transition (EMT) in osteosarcoma.•Glaucocalyxin A prevents TGF-β1-induced EMT by inhibiting Smad2/3 pathway in osteosarcoma.•Glaucocalyxin A inhibits osteosarcoma metastasis to lung in the metastatic model.
Lipopolysaccharide (LPS)-induced liver injury is the main factor in acute liver failure. The current study aims to investigate the protection of limonin, an antioxidant compound from citrus fruit, ...against LPS-induced liver toxicity and elucidate the potential mechanisms. We found that limonin elevated cell viability and reduced LDH release in LPS-treated HepG2 cells. Limonin also inhibited LPS-induced pyroptosis by inhibiting membrane rupture, reducing ROS generation, and decreasing gasdermin D activation. Moreover, limonin inhibited the formation of a NOD-like receptor protein 3 (NLRP3)/Apoptosis-associated speck-like protein containing a CARD (ASC) complex by reducing the related protein expression and the colocalization cytosolic of NLRP3 and caspase-1 and then suppressed IL-1β maturation. Ultimately, we established LPS-induced hepatotoxicity in vivo by using C57BL/6 mice administrated LPS (10 mg/kg) intraperitoneally and limonin (50 and 100 mg/kg) orally. We found that limonin dereased the serum ALT and AST activity and LDH release and increased the hepatic GSH amount in LPS-treated mice. Additionally, the liver histological evaluation revealed that limonin protects against LPS-induced liver damage. We further demonstrated that limonin ameliorated LPS-induced hepatotoxicity by inhibiting pyroptosis via the NLRP3/gasdermin D signaling pathway. In summary, this study uncovered the mechanism whereby limonin mitigated LPS-induced hepatotoxicity and documented that limonin might be a promising candidate drug for LPS-induced hepatotoxicity.
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•Limonin relieved the severity of DSS-induced chronic colitis in mice.•Limonin attenuated DSS-induced chronic colitis by inhibiting PERK-ATF4-CHOP pathway of endoplasmic reticulum ...(ER) stress.•Limonin attenuated DSS-induced chronic colitis by inhibiting NF-κB signaling.•Limonin suppressed PERK-ATF4-CHOP pathway of ER stress and NF-κB signaling in LPS-induced inflammation in vitro.
Inflammatory bowel disease (IBD) is a chronic gastrointestinal inflammation regulated by intricate mechanisms. Limonin, a natural tetracyclic triterpenoid compound, possesses multiple bioactivities including anti-inflammation, anti-cancer and so on. However, the therapeutic potential and the underlying mechanism of limonin on IBD remain unclear. Here, we probe into the effect of limonin on chronic colitis induced by dextran sulfate sodium (DSS) and illustrated the potential mechanisms. We found that limonin relieved the risk and severity of DSS-induced chronic colitis in mice through various aspects including increasing body weight and colon length, decreasing the mortality rate, inhibiting MPO activity and improving colon pathology. Limonin also decreased the production of proinflammatory cytokines TNF-α, IL-1β, IL-6 and the expression of inflammatory proteins COX-2, iNOS in colon tissues from DSS-induced colitis mice. Moreover, limonin attenuated DSS-induced chronic colitis by inhibiting PERK-ATF4-CHOP pathway of endoplasmic reticulum (ER) stress and NF-κB signaling. In vitro, limonin not only decreased LPS-induced higher production of pro-inflammatory cytokines and inflammatory proteins mentioned above by inhibiting NF-κB signaling in macrophage cells RAW264.7, but also suppressed PERK-ATF4-CHOP pathway of ER stress. In summary, our study demonstrated that limonin mitigated DSS-induced chronic colitis via inhibiting PERK-ATF4-CHOP pathway of ER stress and NF-κB signaling. All of this study provides the possibility for limonin as an effective drug for chronic colitis of IBD in the future.
The microstructure and texture of different rolling processes in situ Cu–15Cr sheets are studied. The results show that the second phase Cr in the material gradually become broken, flattened, merged ...and homogenized from dendritic state to oriented thin lath. Meanwhile, the texture in distributed copper matrix grains finally forms Brass {110} , Goss {001} and Copper {112} textures along with Cr phase texture of randomly distributed α-fiber ( fiber) and γ-fiber ( fiber) texture. Based on VPSC (visco-plastic self-consistent model), the texture of cold rolled Cu–15Cr composite is simulated, and the simulation result indicates that obvious twinning effect in the copper matrix appears with a feature of a special texture evolution law of Goss.
Graphic Abstract
The microstructure and texture of different rolling processes in situ Cu–15Cr sheets are studied. The results show that thesecond phase Cr in the material gradually become broken, flattened, merged ...and homogenized from dendritic state to orientedthin lath. Meanwhile, the texture in distributed copper matrix grains finally forms Brass {110} , Goss {001} and Copper {112} textures along with Cr phase texture of randomly distributed α-fiber ( fiber) and γ-fiber( fiber) texture. Based on VPSC (visco-plastic self-consistent model), the texture of cold rolled Cu–15Cr compositeis simulated, and the simulation result indicates that obvious twinning effect in the copper matrix appears with a feature ofa special texture evolution law of Goss. KCI Citation Count: 0
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