Resveratrol attenuated fatty acid synthesis through MAPK-PPAR pathway in red tilapia.

High-fat (HF) diets have been shown to cause hepatic impairment in fish species, but the mode of action, especially the pathways involved, has not yet been determined. In this study, the effects of resveratrol (RES) supplementation on the hepatic structure and fat metabolism of red tilapia (Oreochromis niloticus) were determined. Based on transcriptome and proteomics results, RES was found to promote fatty acid ß-oxidation in the blood, liver, and liver cells associated with apoptosis and the MAPK/PPAR signaling pathway. RES supplementation was found to alter the expression of genes related to apoptosis and fatty acid pathways like blood itga6a and armc5 which were upregulated and downregulated respectively by high-fat feeding while ggh and ensonig00000008711 increased and decreased, respectively, with RES addition. Relative to the PPAR signaling pathway, fabp10a and acbd7 showed a reverse U-shaped tendency, both in different treatments and at different times. Proteomics results demonstrated that MAPK/PPAR, carbon/glyoxylate, dicarboxylate/glycine serine, and threonine/drug-other enzymes/beta-alanine metabolism pathways in the RES group were significantly affected, and Fasn and Acox1 decreased and increased, respectively, with RES addition. Seven subgroups were obtained using scRNA-seq, and enrichment analysis showed that the PPAR signaling pathway was upregulated with RES supplementation. RES significantly increased the expression of the marked genes (pck1) ensonig00000037711, fbp10a, granulin, hbe1, and zgc:136461, which are liver cell-specific genes. In conclusion, RES resulted in significantly enriched DGEs associated with fat metabolism and synthesis via the MAPK-PPAR signaling pathway.

Transcriptome analysis of the response of four immune related organs of tilapia (Oreochromis niloticus) to the addition of resveratrol in feed.

Resveratrol (RES) has been found to have immunological enhancement effects on Oreochromis niloticus. In O. nilocticus, the liver, spleen and kidney act as immune target tissues, while intestine works for nutrition sensing organ. In the present study, we determined RES administration on these immune tissues transcriptomic response in genetically improved farmed tilapia (GIFT), and further analyzed the relationship between transcriptomic response and intestinal microbiota. As results, hepatic hemosiderin and intestinal goblet cells significantly increased with RES addition. Kyoto encyclopedia of genes and genomes (KEGG) pathways associated with herpes simplex virus 1 infection, calcium signaling pathway, cell adhesion molecules, apoptosis, and mitogen-activated protein kinase (MAPK)/peroxisome proliferators-activated receptors (PPAR) signaling pathways were enriched. In particular, the differentially enriched genes (DEGs) associated pathways were present in different sampling tissues, times, and comparisons, interestingly, the PPAR signaling pathway was enriched with increasing time of RES addition. The assembled DEGs presented verified expression in the kidney, liver, spleen, and intestine tissues, and fabp6 was highly expressed in the intestine. Serial DEGs of fatty acid-binding proteins (fabp7, fabp7a, fabp10a) decreased in the liver and kidney, and fabp6 significantly increased in the spleen. With time, the pathways of energy metabolism, glycan biosynthesis, and metabolism decreased and increased in the intestinal metagenome. Some Candidatus branches significantly increased (C. cerribacteria and C. harrisonbacteria) and while others decreased (C. glodbacteria, etc.), whereas C. verstraetearchaeota fluctuated with RES addition. slc27a6 and dbi were negatively correlated with bacteria involved in the lipid, energy, and carbohydrate metabolism pathways. The present study suggests that RES supplementation affected lipid metabolism in immune-related organs may be related to the PPAR signaling pathway.

Alleviative effects of astragaloside IV on cyclophosphamide-induced oxidative damage and immunosuppression in tilapia (Oreochromis niloticus).

Astragaloside IV (ASIV) has effects of antioxidation and immunologic enhancement. However, there are few reports on the application and potential mechanism of ASIV in aquaculture. In this study, we investigated the effect of ASIV on growth, antioxidation, and immune function of tilapia. Tilapia were fed a diet containing 0.1, 0.2, and 0.5 g·kg-1 ASIV for 60 days, followed by an intrapleural injection of 50 mg·kg-1 cyclophosphamide (CTX) to induce oxidative damage and immunosuppression. Then tilapia were weighed and blood, liver, spleen, kidney, and intestinal were collected. The results showed ASIV increased the final weight, relative weight rate, and specific growth rate of tilapia, reduce conversion ratio, and reduced the morphological lesions of tissues. Meanwhile, ASIV alleviated CTX-induced oxidative damage by improving antioxidant activity in serum and tissues and inhibiting lipid peroxidation. Additionally, ASIV attenuated the immunosuppression of tilapia caused by CTX, regulated immunochemical indexes in serum, increased the viability of peripheral blood leukocytes and head kidney macrophages, and restored respiratory burst activity (O2-) in head kidney macrophages and splenocytes. Furthermore, qPCR data showed ASIV up-regulated antioxidant-related gene expression of nrf2, ho-1, gpx3, and cat and immune-related gene expression including C3 and igm. In conclusion, ASIV as a feed additive can not only improve the growth performance but also enhance the antioxidant capacity and immune function of tilapia, which may be associated with the ability of ASIV to scavenge free radicals, reduce lipid peroxidation levels, and stabilize numbers of immune cells.

5-Iodotubercidin inhibits SARS-CoV-2 RNA synthesis.

Coronavirus disease 2019 (COVID-19) is a newly emerged infectious disease caused by a novel coronavirus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The rapid global emergence of SARS-CoV-2 highlights the importance and urgency for potential drugs to control the pandemic. The functional importance of RNA-dependent RNA polymerase (RdRp) in the viral life cycle, combined with structural conservation and absence of closely related homologs in humans, makes it an attractive target for designing antiviral drugs. Nucleos(t)ide analogs (NAs) are still the most promising broad-spectrum class of viral RdRp inhibitors. In this study, using our previously developed cell-based SARS-CoV-2 RdRp report system, we screened 134 compounds in the Selleckchemicals NAs library. Four candidate compounds, Fludarabine Phosphate, Fludarabine, 6-Thio-20-Deoxyguanosine (6-Thio-dG), and 5-Iodotubercidin, exhibit remarkable potency in inhibiting SARS-CoV-2 RdRp. Among these four compounds, 5-Iodotubercidin exhibited the strongest inhibition upon SARS-CoV-2 RdRp, and was resistant to viral exoribonuclease activity, thus presenting the best antiviral activity against coronavirus from a different genus. Further study showed that the RdRp inhibitory activity of 5-Iodotubercidin is closely related to its capacity to inhibit adenosine kinase (ADK).

Discovery and optimization of 2-((1H-indol-3-yl)thio)-N-benzyl-acetamides as novel SARS-CoV-2 RdRp inhibitors.

The emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the global pandemic coronavirus disease (COVID-19), but no specific antiviral drug has been proven effective for controlling this pandemic to date. In this study, several 2-((indol-3-yl)thio)-N-benzyl-acetamides were identified as SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) inhibitors. After a two-round optimization, a new series of 2-((indol-3-yl)thio)-N-benzyl-acetamides was designed, synthesized, and evaluated for SARS-CoV-2 RdRp inhibitory effect. Compounds 6b2, 6b5, 6c9, 6d2, and 6d5 were identified as potent inhibitors with IC50 values of 3.35 ± 0.21 µM, 4.55 ± 0.2 µM, 1.65 ± 0.05 µM, 3.76 ± 0.79 µM, and 1.11 ± 0.05 µM, respectively; the IC50 of remdesivir (control) was measured as 1.19 ± 0.36 µM. All of the compounds inhibited RNA synthesis by SARS-CoV-2 RdRp. The most potent compound 6d5, which showed a stronger inhibitory activity against the human coronavirus HCoV-OC43 than remdesivir, is a promising candidate for further investigation.

Discovery of Novel Biased Opioid Receptor Ligands through Structure-Based Pharmacophore Virtual Screening and Experiment.

Gi -protein-biased agonists with minimal ß-arrestin recruitment represent opportunities to overcome the serious adverse effects of human mu opioid receptor (µ-OR) agonists and developing alternative and safe treatments for pain. In order to discover novel non-morphinan opioid receptor agonists, we applied hierarchical virtual screening of our in-house database against a pharmacophore based on modeling the active conformations of opioid receptors. We discovered an initial hit compound, a novel µ-OR agonist with a pyrazoloisoquinoline scaffold. We applied computational R-group screening to this compound and synthesized 14 derivatives predicted to be the best. Of these, a new Gi -protein-biased compound, 1-{5-(3-chlorophenyl)-7,8-dimethoxy-3-[4-(methylsulfonyl)benzyl]-3H-pyrazolo[3,4-c]isoquinolin-1-yl}-N,N-dimethylmethanamine, showed an EC50 value of 179 nm against the µ-OR. This resulted in significant pain relief for mice in the phase II period of formalin response tests. This study provides a new strategy to identify diverse sets of promising compounds that might prove useful for the development of drugs that target other G-protein-coupled receptors.

Identification of Triptophenolide from Tripterygium wilfordii as a Pan-antagonist of Androgen Receptor.

A compound, triptophenolide, derived from Tripterygium wilfordii was identified as an antiandrogen. Triptophenolide inhibits the activity of both wild-type and F876L mutant androgen receptors. Triptophenolide exhibits its antiandrogenic activity through competitive binding with androgen in the hormone-binding pocket, decreasing the expression of androgen receptor, and reducing the nuclear translocation of androgen receptor.