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All drugs that can penetrate the blood-brain barrier (BBB) may lead to mental state changes, including the widely used anti-infective drug sulfamethoxazole (SMZ). Herein, we investigated whether lycopene (LYC) could ameliorate SMZ-induced brain injury and the postulated mechanisms involved. A total of 120 grass carps were exposed under SMZ (0.3 μg/L, waterborne) or LYC (10 mg/kg fish weight, diet) or their combination for 30 days. Firstly, brain injury induced by SMZ exposure was suggested by the damage of BBB (decreases of Claudins, Occludin and Zonula Occludens), and the decrease of neurotransmitter activity (AChE). Through inducing oxidative stress (elevations of malondialdehyde and 8-hydroxy-2 deoxyguanosine, inhibition of glutathione), SMZ increased the intra-nuclear level of NF-κB and its target genes (TNF-α and interleukins), creating an inflammatory microenvironment. As a positive feed-back mechanism, apoptosis begins with activation of pro-death proteins (Bax/Bcl-2) and activation of caspases (caspase-9 and caspase-3). Meanwhile, a compensatory upregulation of constitutive Nrf2 and its downstream antioxidative gene expression (NAD(P)H Quinone Dehydrogenase 1 and Heme oxygenase 1) and accelerated autophagy (increases of autophagy-related genes and p62 inhibition) were activated as a defense mechanism. Intriguingly, under SMZ stress, LYC co-administration decreased NF-κB/apoptosis cascades and restored Nrf2/autophagy levels. The neuroprotective roles of LYC make this natural compound a valuable agent for prevention SMZ stress in environment. This study suggests that LYC might be developed as a potential candidate for alleviating environmental SMZ stress in aquaculture. • Sulfamethoxazole exposure leads to oxidative stress, inflammation and apoptosis in the brain. • Lycopene supplementation ameliorates brain damage induced by Sulfamethoxazole. • Lycopene exerts neuroprotection by rebalance of NF-κB/Nrf2 pathway. [ABSTRACT FROM AUTHOR]

(−)-Epigallocatechin-3-gallate (EGCG), a constituent of green tea, has been suggested to have numerous health-promoting effects. On the other hand, high-dose EGCG is able to evoke hepatotoxicity. In the present study, we elucidated the responses of hepatic major antioxidant enzymes and nuclear factor erythroid 2-related factor 2 (Nrf2) rescue pathway to high-dose levels of EGCG in Kunming mice. At a non-lethal toxic dose (75 mg/kg, i.p.), repeated EGCG treatments markedly decreased the levels of superoxide dismutase, catalase, and glutathione peroxidase. As a rescue response, the nuclear distribution of Nrf2 was significantly increased; a battery of Nrf2-target genes, including heme oxygenase 1 (HO1), NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione S-transferase (GST), and those involved in glutathione and thioredoxin systems, were all up-regulated. At the maximum tolerated dose (45 mg/kg, i.p.), repeated EGCG treatments did not disturb the major antioxidant defense. Among the above-mentioned genes, only HO1, NQO1, and GST genes were significantly but modestly up-regulated, suggesting a comprehensive and extensive activation of Nrf2-target genes principally occurs at toxic levels of EGCG. At a lethal dose (200 mg/kg, i.p.), a single EGCG treatment dramatically decreased not only the major antioxidant defense but also the Nrf2-target genes, demonstrating that toxic levels of EGCG are able to cause a biphasic response of Nrf2. Overall, the mechanism of EGCG-triggered hepatotoxicity involves suppression of major antioxidant enzymes, and the Nrf2 rescue pathway plays a vital role for counteracting EGCG toxicity. [ABSTRACT FROM AUTHOR]

Freshwater environmental antibiotic pollution is becoming more severe because of the irregular use of sulfonamide antibiotics. Sulfamethoxazole (SMZ) is a kind of antibiotic that can cause harm to the urinary systems of organisms. However, the toxic impacts of environment-related concentrations of antibiotics in fish have not been thoroughly studied. Lycopene (LYC) has the property of alleviating antibiotic toxicity by diminishing oxidative stress and inflammation. This investigation is intended to examine the instrument of the mitigative part of LYC on SMZ-caused renal inflammatory injury in grass carp. Grass carp were born with SMZ (0. 3 μg L−1) and LYC (10 mg/kg body weight) for 30 days. Serum was used to measure creatinine (CREA) and urea nitrogen (BUN) contents; what is more, kidneys were used to measure histological structure, oxidative stress indicators, relative expressions of cytokines, and inflammatory factors. We found that SMZ exposure significantly increased oxidative stress, characterized by decreased catalase activity (CAT) and superoxide dismutase (SOD). In addition, inflammation-related factors: interleukin (IL-18, IL-6, and IL-1β), an apoptotic speck-containing protein with a card (ASC), NOD-like receptor protein3 (NLRP3), cysteinyl aspartate specific proteinase-1 (caspase-1), tumor necrosis factor-α (TNF-α), and nuclear factor-activated B cells (NF-κB) expression increased significantly contrasted with those control group. Inflammatory reactions and ultrastructural changes accompany. LYC administration alleviated the changes mentioned above. In conclusion, In conclusion, these results suggest a protective effect of LYC dietary supplements against kidney damage caused by SMZ. LYC is expected to prevent and treat oxidative stress and chronic inflammation caused by antibiotics as a critical component in the fish breeding diet. [Display omitted] • Sulfamethoxazole exposure caused in the mechanism of the inflammasome in grass carp kidneys. • NLRP3 inflammasome activates and secretes active Caspase-1 and IL-1β. • Lycopene relieves sulfamethoxazole caused inflammation and pyroptosis through the NF-κB and NLRP3 signaling pathway. [ABSTRACT FROM AUTHOR]

Rupture of vulnerable plaque and secondary thrombosis caused by atherosclerosis are one of the main causes of acute cardiovascular and cerebrovascular events, and it is urgent to develop an in-situ, noninvasive, sensitive and targeted detection method at molecular level. We chose CD44, a specific receptor highly expressed on the surface of macrophages, as the target of the molecular probe, and modified the CD44 ligand HA onto the surface of Gd 2 O 3 @MSN, constructing the MRI imaging nanoprobe HA-Gd 2 O 3 @MSN for targeted recognition of atherosclerosis. The fundamental properties of HA-Gd 2 O 3 @MSN were initially investigated. The CCK-8, hemolysis, hematoxylin-eosin staining tests and blood biochemical assays confirmed that HA-Gd 2 O 3 @MSN possessed excellent biocompatibility. Laser confocal microscopy, cellular magnetic resonance imaging, flow cytometry and immunohistochemistry were used to verify that the nanoprobes had good targeting properties. The in vivo targeting performance of the nanoprobes was further validated by employing a rabbit atherosclerosis animal model. In summary, the synthesized HA-Gd 2 O 3 @MSN nanoprobes have excellent biocompatibility properties as well as good targeting properties. It could provide a new technical tool for early identification of atherosclerosis. • Gadolinium-doped mesoporous silica reduces the toxicity of free Gd3+ and improves the biocompatibility of nanoprobes. • The particle surface was modified by HA to improve the targeting performance of the nanoprobes. • Nanoparticles with excellent pore size structure can further lay the foundation for drug-carrying treatment of plaques. [ABSTRACT FROM AUTHOR]

Abstract: Thioredoxin reductase (TrxR) is a target for cancer therapy and the anticancer mechanism of cisplatin involves TrxR inhibition. We hypothesize that the anticancer drug nedaplatin (NDP), an analogue of cisplatin and a second-generation platinum complex, also targets TrxR. Furthermore, we investigate whether the therapeutic efficacy of NDP can be enhanced by simultaneous modulation of 1) TrxR, via NDP, and 2) glutathione (GSH), via the GSH synthesis inhibitor buthionine sulfoximine (BSO). Mice bearing ascitic hepatoma 22 (H22) cells were treated with NDP alone or NDP plus BSO. TrxR activity of H22 cells was inhibited by NDP in a dose-dependent manner. A high correlation between the inhibition of TrxR activity at 6h and the inhibition of ascitic fluid volume at 72h was established (r=0.978, p <0.01). As an adaptive response, the viable ascitic cancer cells after NDP treatment displayed an enlarged cell phenotype, assembled with several-fold more antioxidant enzymes and GSH-predominant non-protein free thiols. This adaptive response was largely eliminated when BSO was co-administered with NDP, leading to the decimation of the H22 cell population without enhancing renal toxicity, since at this dose, NDP did not inhibit renal TrxR activity. In conclusion, the pharmacological effect of NDP involves TrxR inhibition, and the adaptive response of NDP-treated ascitic H22 cells can be efficiently counteracted by BSO. Simultaneous modulation of TrxR and GSH on ascitic H22 cells using NDP plus BSO greatly enhances therapeutic efficacy as compared with the single modulation of TrxR using NDP alone. [Copyright &y& Elsevier]

Doxorubicin (DOX), a chemotherapeutic drug, could relieve the progressions of various diseases. However, its clinical application is limited due to its cardiotoxicity. This study aimed to investigate the effects of afzelin (a flavonol glycoside found in Houttuynia cordata) on the cardiotoxicity induced by DOX. In ex-vivo, H9C2 cells were incubated with 20, 40, or 80 μM afzelin for 12 h, followed by the treatment with 1 μM DOX for 12 h. In vivo, C57BL/6 J mice were intraperitoneally injected with 4 mg/kg/day DOX on days 1, 7, and 14. Meanwhile, starting from day 1, mice were intragastrically administrated with 5 mg/kg/day or 10 mg/kg/day afzelin for 20 days. The cardiac function of mice was evaluated by detecting hemodynamic parameters using the M-mode echocardiography. DOX decreased the cell survival rate, and elevated apoptotic rate, as well as induced the oxidative stress and mitochondrial dysfunction in H9C2 cells. All these changes were alleviated by afzelin treatment in a concentration-dependent manner. The results were further proven by the mitigation of cardiac injury in vivo, as evidenced by the elevation of fractional shortening, heart weight/tibia length, and the rate of the increase/decrease of left ventricular pressure in mice subjected to DOX-induced cardiotoxicity. Furthermore, afzelin upregulated the expression of p-AMP-activated protein kinase alpha (AMPKα) and sirtuin1 (SIRT1). Dorsomorphin (an AMPKα inhibitor) abrogated the anti-cardiotoxicity effects of afzelin in H9C2 cells induced by DOX. Afzelin protected against DOX-induced cardiotoxicity by promoting the AMPKα/SIRT1 signaling pathway. • Afzelin ameliorates doxorubicin-induced cardiac injury in vivo. • Afzelin dampens the doxorubicin-induced injury of cardiomyocyte in ex-vivo. • Afzelin promotes the AMP-activated protein kinase alpha /sirtuin1 signaling pathway. [ABSTRACT FROM AUTHOR]

Ascorbic acid is very important to human health because of its excellent antioxidant effect. Developing sensitive and on-site detection methods is therefore in high demand. In this work, a portable paper-based colorimetric sensor with a smartphone platform with an ultrahigh sensitivity has been designed for on-site and quantitative analysis of ascorbic acid based on AuNPs nanozyme activity. The developed excellent peroxidase-like nanozymes, could effectively catalyze the oxidation of chromogenic substrates by H 2 O 2. Herein, the AuNPs nanozyme activity are embedded on paper pieces to construct paper-based microfluidic chips for visual detection. Meanwhile, a smartphone platform is integrated for the signal readout. Using ascorbic acid as an analyte model, the proposed paper-based analysis platform shows a reliable and sensitive detection of ascorbic acid with a low detection limit of 0.406 μmol/L. The platform also works well in various real samples. This analysis method is facile in design, showing a great application potential for on-site and mass screening of ingredients in the environment and in foods. [Display omitted] • The mimics enzymes that has the high catalytic activity of natural enzymes. • A paper-based microfluidic chip was combined with a smartphone for visual detection. • The color changing of solution and paper chips can be simply visualized by the naked eye. • RGB intensities were measured to quantify ascorbic acid concentration. • The on-site device for AA determining based on smartphone, paper chips and AuNPs was developed. [ABSTRACT FROM AUTHOR]

Abstract: Our previous studies in mice revealed that two weeks short-term toxicity of sodium selenosulfate was significantly lower than that of sodium selenite, but selenium repletion efficacy of both compounds was equivalent. In addition, we showed that sodium selenosulfate reduced nephrotoxicity of cisplatin (CDDP) without compromising its anticancer activity, thus leading to a dramatic increase of cancer cure rate from 25% to 75%. Hydration has been used in clinical practice to reduce CDDP-induced nephrotoxicity, but it cannot mitigate CDDP-induced gastrointestinal toxicity. The present work investigated whether sodium selenosulfate is a potential preventive agent for the gastrointestinal toxicity. In tumor-bearing mice, sodium selenosulfate was administered at a dose of 9.5μmol/kg daily for 11days, CDDP alone resulted in diarrhea by 88% on day 12, whereas the co-administration of CDDP and sodium selenosulfate dramatically reduced diarrhea to 6% (p <0.0001). Such a prominent protective effect promoted us to evaluate the safety potential of long-term sodium selenosulfate application. Mice were administered with sodium selenosulfate or sodium selenite for 55days at the doses of 12.7 and 19μmol/kg. The low-dose sodium selenite caused growth suppression and hepatotoxicity which were aggravated by the high-dose, leading to 40% mortality rate, but no toxic symptoms were observed in the two sodium selenosulfate groups. Altogether these results clearly show that sodium selenosulfate at an innocuous dose can markedly prevent CDDP-induced gastrointestinal toxicity. [Copyright &y& Elsevier]

• In this study, we firstly find that PI3K was essential for TNF-induced necroptotic signaling transduction, including necrosome formation and phosphorylation or oligomerization of RIP1, RIP3 and MLKL in response to TNF stimulation. As PI3K catalytic subunit p110 bound RIP3 and mediated RIP3-dependent necroptosis in RIP1-knockdown L929 cells, it is reasonable to raise the possibility that PI3K mediates TNF-induced necroptosis via targeting RIP3. Necroptosis is a recently identified programmed cell death, which is initiated by receptor-interacting serine/threonine-protein kinase 1 (RIP1), RIP3 and mixed-lineage kinase domain-like protein (MLKL). It has been reported that necroptosis induced by tumor necrosis factor (TNF) was inhibited by the inhibitor of phosphatidylinositol-3-kinase (PI3K) and its substrate protein AKT, indicating that PI3K-AKT signaling pathway was involved in mediating TNF-induced necroptosis, whereas it is unclear how PI3K initiates necroptosis. In this study, we found that TNF-induced necroptosis was inhibited by chemical inhibition or genetic deletion of PI3K. Moreover, knockdown of p110α, the catalytic subunit of PI3K, significantly suppressed the phosphorylation of PI3K substrate protein AKT, and TNF-induced necroptosis was blocked by AKT inhibitors. Furthermore, we found that p110α knockdown also suppressed the phosphorylation and oligomerization of RIP1, RIP3 and MLKL in response to TNF stimulation. In addition to the critical role in mediating TNF-induced necrosome formation, p110α was also essential for the spontaneous phosphorylation of RIP1 and RIP3. Finally, we found that p110α bound to RIP3, but not RIP1, to form protein complex in the process of TNF-induced necroptosis, and mediated TNF-induced necroptosis in the absence of RIP1. Our results demonstrate that PI3K is essential for TNF-induced necroptosis, which may act as the partner of RIP3 to initiate the activation of RIP1-RIP3-MLKL signal pathway and the subsequent necroptosis. [ABSTRACT FROM AUTHOR]