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To develop new anti-metastasis chemotherapeutic drugs, a series of flurbiprofen (FLP) and zaltoprofen (ZTP) platinum(IV) complexes targeting COX-2, PD-L1 and DNA was prepared and investigated. Complex 2 with dual FLP ligands displays promising antitumor activities

Metastasis is a major contributor of death in cancer patients, and there is an urgent need for effective treatments of metastatic malignancies. Herein, ketoprofen (KP) and loxoprofen (LP) platinum(IV) complexes with antiproliferative and antimetastatic properties were designed and prepared by integrating chemotherapy and immunotherapy targeting cyclooxygenase-2 (COX-2), matrix metalloproteinase-9 (MMP-9), and programmed death ligand 1 (PD-L1), besides DNA. A mono-KP platinum(IV) complex with a cisplatin core is screened out as a candidate possessing potent anti-proliferative and anti-metastasis activities both in vitro and in vivo. It induces serious DNA damage and further leads to high expression of γ-H2AX and p53. Moreover, it promotes apoptosis of tumor cells through mitochondrial apoptotic pathway Bcl-2/Bax/caspase3. Then, COX-2, MMP-9, NLRP3, and caspase1 as pivotal enzymes igniting inflammation and metastasis are obviously inhibited. Notably, it significantly improves immune response through restraining the expression of PD-L1 to increase CD3+ and CD8+ T infiltrating cells in tumor tissues.

To develop new chemotherapeutics with anti-metastasis properties, a series of multi-specific niflumic acid (NFA) platinum(IV) complexes with DNA damage, inflammation inhibition, immunity activation, and angiogenesis suppression mechanisms were designed, synthesized and evaluated as novel antitumor agents. The dual NFA platinum(IV) complex with a cisplatin core showed promising antitumor activities both

Li L, Chen Y, Wang Q, et al. Int J Nanomedicine. 2021;16:5513–5529. It has been brought to the authors attention that the control groups of antitumor activities in vivo overlapped with those from the authors previously published article, Chen Y, Wang Q, Li Z, et al. Dalton Trans. 2020;49:5192–5204 (https://doi.org/10.1039/D0DT00424C) which was cited as reference 39. These two works both belonged to the topic of platinum(IV) antitumor complexes with inflammation inhibitory competence, but focused on two important and different aspects. Dalton Trans. 2020;49:5192–5204 (Ref 39) reported the free naproxen platinum(IV) hybrids as potent antitumor compounds. To further improve antitumor activities and decrease toxicities of naproxen platinum(IV) complexes, albumin-encapsulated nanoparticles based on naproxen platinum(IV) complexes were prepared and investigated in this work. In order to compare the antitumor activities of the albumin-encapsulated nanoparticles and free naproxen platinum(IV) complexes more clearly, the experiments of the antitumor activities in vivo in both works were carried out simultaneously, and the same positive and negative control groups (cisplatin, oxaliplatin, blank) were shared. The authors wish to cite and declare in the associated Figures 4, 5 and 10 the following, “Reprinted with permission from Chen et al. Dalton Trans. 2020;49(16):5192–5204. Copyright © 2020. The Royal Society of Chemistry.39” In addition, the authors regret that an error occurred during the preparation of Figure 5C. Incorrect images for the H&E staining slices of Heart, Saline group and Liver, Compound 1 treated group were used, following an accidental mix-up of the data during the image compilation, and the correct images were reuploaded. The authors sincerely apologize for the error and guarantee that this correction has no impact to the interpretation of the presented results and conclusions of this work. The correct note section for Figure 4 on page 5522 is as follows. Notes: Results are presented as the mean ± SD (n=6). *P

Copper is a common component of industrial heavy metal waste and a major component of some fish medicines, which can cause oxidative stress and damage the health of farmed fish. The Nrf2 signaling pathway is an important pathway related to the oxidative stress on vertebrates. Exploring the effect of copper on the Nrf2 signaling pathway in fish hepatocytes would help improve the understanding of the molecular mechanism of antioxidants in fish hepatocytes and provide theoretical data for relevant toxicological research. Adult tilapia were cultured under properly controlled conditions for two weeks to adapt to laboratory culture conditions. Primary tilapia hepatocytes were obtained by cell culture. MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay was used to detect the effect of copper ions on the viability of tilapia hepatocytes. The lipid peroxidation level (MDA) and antioxidant ability of tilapia hepatocytes (SOD and CAT activity) were detected. Quantitative PCR (qPCR) was used to detect the differential expression of each gene (Nrf2, Keap1a, Keap1b, CuZnSOD, MnSOD, HO-1, and GSTA) in the Nrf2 signaling pathway. The results suggested that after treatment with 100 μM copper ions for 4 h, 8 h, and 24 h, the viability of hepatocytes significantly decreased (p < 0.05). LDH and MDA after 8 h and 24 h treatment were significantly higher than those in the control group (p < 0.05). CAT activity significantly decreased after 4 h (p < 0.05), and SOD activity significantly decreased after 8 h and 24 h (p < 0.05). The results of qPCR showed that the expression of MnSOD significantly increased after a treatment with copper ions for 4 h, and the expression of Nrf2, Keap1a, CuZnSOD, HO-1 as well as GSTA significantly increased after a treatment with copper ions for 8 h, compared with the control group (p < 0.05). After being treated with copper ions for 24 h, the expression of Nrf2 and CuZnSOD significantly increased compared with the control group (p < 0.05). There was no significant difference in the expression of Keap1b or CAT at each time point. In conclusion, with copper ions exposure, the viability of tilapia hepatocytes was reduced, causing lipid peroxidation, a reduction in the antioxidant capacity of cells, the activation of the Nrf2 signaling pathway, and the increase in the expression of most genes in this pathway, which are defensive responses of hepatocytes to oxidative stress caused by copper ions. This study can provide theoretical data for related toxicological research.

Summer outbreaks of the hepatobiliary syndrome in fish impose a heavy burden on aquaculture in China. Curcumin is a polyphenol with antioxidant activity that has been used to protect the health of fish livers, but the mechanism underlying its protective effect is unclear. In this study, an in vitro model of hepatocyte oxidative damage in Oreochromis niloticus was established using H2O2. Treatment with 5 mM H2O2 for 2.5 h markedly reduced cell viability and antioxidant activity and elevated lactate dehydrogenase (LDH) activity, indicating conditions that can be used to establish an oxidative stress model. Under H2O2 stress, curcumin pretreatment significantly maintained cell viability, reduced malondialdehyde (MDA) levels, and increased superoxide dismutase (SOD) activity. RNA-seq results showed that acute H2O2 treatment resulted in minor changes in gene expression, whereas curcumin changed the expression profile and affected cytochrome P450 (Cyp 450), glutathione (GSH) metabolism, and the peroxisome proliferator-activated receptor (PPAR) signaling pathway. Several critical antioxidant defense signaling pathways were identified, and altered expression was confirmed by q-PCR. These results indicate that curcumin might upregulate PPAR expression by increasing Cyp2J2 expression. Further experiments showed that curcumin can upregulate the Nrf2-Keap1 signaling pathway at the transcriptional level, and this upregulation can induce downstream defense genes, including glutamate cysteine ligase catalytic subunit(GCLC) and glutamate cysteine ligase modifier subunit (GCLM), and thereby promote GSH synthesis and the expression of related antioxidases. This study might shed light on the effects of curcumin on the prevention and alleviation of liver diseases in fish.

Curcumin is a polyphenol with antioxidant activity that has been used to protect the health of fish livers. Our previous studies about comparative transcriptome have shown that curcumin can enhance the Nrf2-Keap1 signaling pathway and induce downstream anti-stress genes to maintain cell viability. However, the possible role of miRNAs in the protective mechanism of curcumin is not understood. In this study, the tilapia hepatocyte H2O2 stress model was used, and the miRNA expression profile for four groups (control group, curcumin group, H2O2 group, and protection group) were established by high-throughput sequencing. In our results, 278–333 types of Oreochromis niloticus miRNAs, 309–543 types of conserved miRNAs, and 535–746 types of novel miRNAs were identified in different samples. Differentially expressed miRNAs were identified by comparing miRNA expression profiles among the four groups. The expression levels were confirmed by q-PCR. The target genes of these differentially expressed miRNAs were predicted, and their functional annotations were enriched by GO and KEGG analysis, which revealed that many target genes were involved in “response to stimulus” and “antioxidant activity” in each pair of groups. Several miRNAs related to oxidative stress showed differential expression. For example, in the H2O2 group, the expression of miR-122 was decreased, and the expression of miR-21 and miR-489 increased significantly. In the curcumin group, the expression of miR-153b was decreased, and the expression of miR-200a and miR-29 was increased significantly. miR-153b, miR-200a, and miR-29 may be involved in the regulation of the Nrf2-Keap1 signaling pathway by curcumin. This work might provide insights into the molecular mechanisms of miRNA regulation of curcumin on the prevention and alleviation of liver diseases in fish.

Gonadotropin-releasing hormone (GnRH) is a crucial peptide for the regulation of reproduction. Using immunological techniques, we investigated the presence of GnRH in horseshoe crab Tachypleus tridentatus. Octopus GnRH-like immunoreactivity, tunicate GnRH-like immunoreactivity, and lamprey GnRH-I-like immunoreactivity were detected in the neurons and fibers of the protocerebrum. However, no mammal GnRH-like immunoreactivity or lamprey GnRH-III-like immunoreactivity was observed. Our results suggest that a GnRH-like factor, an ancient peptide, existed in the brain of T. tridentatus and may be involved in the reproductive endocrine system.

This study was designed to determine whether a transjugular intrahepatic portosystemic shunt (TIPS) combined with embolotherapy was superior to TIPS alone.Seventy-nine patients were included in the study (43 in the TIPS and embolotherapy group and 36 in the TIPS alone group). Embolotherapy was performed after TIPS using coils and a tissue adhesive agent. The portosystemic pressure gradient (PPG) after TIPS was lower than 12 mm Hg in all patients. Multivariate analyses were performed using a Cox regression model, and the probabilities of survival and rebleeding were estimated with the Kaplan-Meier method.Baseline patient survey data showed similar distributions in both groups. The mean follow-up time was 45.6 months (range: 1 to 85.6 mo). There were no significant differences in the incidences of rebleeding (P=0.889), stent revision (P=0.728), encephalopathy (P=0.728), the cumulative survival rate (P=0.552), or the probability of being free of rebleeding (P=0.806) between the 2 groups. Of 9 patients with rebleeding after TIPS plus embolotherapy, 7 had a history of esophageal variceal bleeding and 2 had gastric variceal bleeding. Of 8 patients with rebleeding after TIPS alone, 4 had a history of esophageal variceal bleeding and 4 had gastric variceal bleeding (P=0.247). Multivariate analysis showed that PPG after TIPS was an independent predictor of rebleeding (P=0.036). Age and Model of End-stage Liver Disease score were independent predictors of survival (P=0.048 and 0.037).The results suggest that TIPS with embolotherapy cannot reduce the risk of rebleeding if PPG is less than 12 mm Hg after TIPS. PPG after TIPS is an independent predictor of rebleeding.