Docosahexaenoic Acid-Acylated Astaxanthin Esters Exhibit Superior Renal Protective Effect to Recombination of Astaxanthin with DHA via Alleviating Oxidative Stress Coupled with Apoptosis in Vancomycin-Treated Mice with Nephrotoxicity.

Prevention of acute kidney injury caused by drugs is still a clinical problem to be solved urgently. Astaxanthin (AST) and docosahexaenoic acid (DHA) are important marine-derived active ingredients, and they are reported to exhibit renal protective activity. It is noteworthy that the existing forms of AST in nature are mainly fatty acid-acylated AST monoesters and diesters, as well as unesterified AST, in which DHA is an esterified fatty acid. However, no reports focus on the different bioactivities of unesterified AST, monoesters and diesters, as well as the recombination of DHA and unesterified AST on nephrotoxicity. In the present study, vancomycin-treated mice were used to evaluate the effects of DHA-acylated AST monoesters, DHA-acylated AST diesters, unesterified AST, and the recombination of AST and DHA in alleviating nephrotoxicity by determining serum biochemical index, histopathological changes, and the enzyme activity related to oxidative stress. Results found that the intervention of DHA-acylated AST diesters significantly ameliorated kidney dysfunction by decreasing the levels of urea nitrogen and creatinine, alleviating pathological damage and oxidative stress compared to AST monoester, unesterified AST, and the recombination of AST and DHA. Further studies revealed that dietary DHA-acylated AST esters could inhibit the activation of the caspase cascade and MAPKs signaling pathway, and reduce the levels of pro-inflammatory cytokines. These findings indicated that the administration of DHA-acylated AST esters could alleviate vancomycin-induced nephrotoxicity, which represented a potentially novel candidate or therapeutic adjuvant for alleviating acute kidney injury.

Absorption, Pharmacokinetics, Tissue Distribution, and Excretion Profiles of Sea Cucumber-Derived Sulfated Sterols in Mice.

Sea cucumber-derived sulfated sterols exhibited more significant bioactivities compared to plant sterols due to the distinctive structure of the sulfate group at the C-3 position; however, their absorption, pharmacokinetics, tissue distribution, and excretion profiles are unknown, which limits the analysis of molecular mechanisms related to their unique activities. In this study, the absorption characteristics of sea cucumber sterols were determined by oral gavage administration, and their pharmacokinetics, excretion, and tissue distribution were studied by tail vein injection. The results showed that SS1 and SS2 reached the peak at 3 h (20.14 ± 1.2 µg/mL) and 4 h (13.32 ± 0.9 µg/mL) in serum, respectively, after oral gavage administration, suggesting the faster absorption rate of SS1 than SS2 due to the difference in the side-chain groups. Besides, lipid-containing food media improved the digestion and absorption rates of sea cucumber sterols. Moreover, SS1 exhibited a relatively longer duration of efficacy than SS2, and they were almost completely excreted within 9 h through urine. Additionally, sea cucumber sterols were found to be mainly accumulated in the liver (P < 0.05), followed by the kidney and spleen. These findings might provide a theoretical basis for the research and development of functional foods and nutraceuticals associated with sea cucumber sterols.

Characterization, stability, digestion and absorption of a nobiletin nanoemulsion using DHA-enriched phosphatidylcholine as an emulsifier in vivo and in vitro.

The emulsification ability of phospholipids might be associated with fatty acid composition. However, there is no research regarding the emulsification ability of marine-derived phospholipids rich in docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). The present study developed a nanoemulsion delivery system using DHA-enriched phosphatidylcholine as an emulsifier to deliver the poorly soluble ingredient nobiletin. The prepared nobiletin-loaded nanoemulsion was stable, with a small particle size of approximately 200 nm, a polydispersity index of 0.082, and a neutral zeta potential. The nobiletin-loaded nanoemulsion exhibited high lipolysis ability in in vitro experiments. Moreover, the nobiletin-encapsulated nanoemulsion was digested quickly and entered the serum faster than the oil suspension. There was a high distribution of nobiletin in organs such as the liver, brain, kidney, and spleen in the emulsion group after oral administration for 2 h. The findings provided a nanoemulsion delivery system to increase the bioavailability of nobiletin in vitro and in vivo.

EPA-enriched plasmalogen attenuates the cytotoxic effects of LPS-stimulated microglia on the SH-SY5Y neuronal cell line.

Microglia plays an important role in the production of inflammation in the central nervous system. Excessive nerve inflammation can cause neuronal damage and neurodegenerative disease. It has been shown that EPA-enriched ethanolamine plasmalogen (EPA-PlsEtn) significantly inhibited the expressions of inflammatory factors and suppressed neuronal loss in a rat model of Alzheimer's disease. However, whether EPA-PlsEtn protects against neuronal loss by inhibiting the activation of microglia is still not clear. Therefore, we examined the effect of PlsEtn on SH-SY5Y cells incubated by conditioned medium from LPS-induced BV2 cells as a neuroinflammation model. Results showed that pre-incubation of LPS-induced BV2 cells with PlsEtn significantly improved the viability of SH-SY5Y cells by reducing the early apoptosis. The increasing production of NO and TNF-α in BV2 cells was reversed by PlsEtn treatment, while the decreasing level of IL-10 was raised. Polarization toward M1 phenotype and activation of NLRP3 inflammasome pathways are attenuated significantly by pre-treatment of PlsEtn in LPS-induced BV2 cells. The study provides evidence for a positive effect of PlsEtn on neuroprotection and the inhibition of neuroinflammation, and PlsEtn may be explored as a potential functional ingredient with neuroprotection effects.

Sterol sulfate alleviates atherosclerosis via mediating hepatic cholesterol metabolism in ApoE-/- mice.

Compared with terrestrial organisms, the sterols in sea cucumber exhibit a sulfate group at the C-3 position. Our previous study demonstrated that dietary sterol sulfate was superior to phytosterol in alleviating metabolic syndrome by ameliorating inflammation and mediating cholesterol metabolism in high-fat-high-fructose diet mice, which indicated its potential anti-atherosclerosis bioactivity. In the present study, administration with sea cucumber-derived sterol sulfate (SCS) significantly decreased the cholesterol level in oleic acid/palmitic acid-treated HepG2 cells, while no significant changes were observed in the triacylglycerol level. RNA-seq analysis showed that the metabolic changes were mostly attributed to the steroid biosynthesis pathway. ApoE-/- mice were used as an atherosclerosis model to further investigate the regulation of SCS on cholesterol metabolism. The results showed that SCS supplementation dramatically reduced atherosclerotic lesions by 45% and serum low-density lipoprotein cholesterol levels by 59% compared with the model group. Dietary SCS inhibited hepatic cholesterol synthesis via downregulating SREBP-2 and HMGCR. Meanwhile, SCS administration increased cholesterol uptake via enhancing the expression of Vldlr and Ldlr. Noticeably, SCS supplementation altered bile acid profiles in the liver, serum, gallbladder and feces, which might cause the activation of FXR in the liver. These findings provided new evidence about the high bioactivity of sterols with the sulfate group on atherosclerosis.

Trichoderma: A Treasure House of Structurally Diverse Secondary Metabolites With Medicinal Importance.

Fungi play an irreplaceable role in drug discovery in the course of human history, as they possess unique abilities to synthesize diverse specialized metabolites with significant medicinal potential. Trichoderma are well-studied filamentous fungi generally observed in nature, which are widely marketed as biocontrol agents. The secondary metabolites produced by Trichoderma have gained extensive attention since they possess attractive chemical structures with remarkable biological activities. A large number of metabolites have been isolated from Trichoderma species in recent years. A previous review by Reino et al. summarized 186 compounds isolated from Trichoderma as well as their biological activities up to 2008. To update the relevant list of reviews of secondary metabolites produced from Trichoderma sp., we provide a comprehensive overview in regard to the newly described metabolites of Trichoderma from the beginning of 2009 to the end of 2020, with emphasis on their chemistry and various bioactivities. A total of 203 compounds with considerable bioactivities are included in this review, which is worth expecting for the discovery of new drug leads and agrochemicals in the foreseeable future. Moreover, new strategies for discovering secondary metabolites of Trichoderma in recent years are also discussed herein.

New Enantiomers of a Nor-Bisabolane Derivative and Two New Phthalides Produced by the Marine-Derived Fungus Penicillium chrysogenum LD-201810.

Marine-derived fungi are a treasure house for the discovery of structurally novel secondary metabolites with potential pharmaceutical value. In this study, a pair of new nor-bisabolane derivative enantiomers (±)-1 and two new phthalides (4 and 5), as well as four known metabolites, were isolated from the culture filtrate of the marine algal-derived endophytic fungus Penicillium chrysogenum LD-201810. Their structures were established by detailed interpretation of spectroscopic data (1D/2D NMR and ESI-MS). The optical resolution of compound (±)-1 by chiral HPLC successfully afforded individual enantiomers (+)-1 and (-)-1, and their absolute configurations were determined by TDDFT-ECD calculations. Compound (±)-1 represents the first example of bisabolane analogs with a methylsulfinyl substituent group, which is rare in natural products. All of the isolated compounds 1-7 were evaluated for their cytotoxic activity against A549, BT-549, HeLa, HepG2, MCF-7, and THP-1 cell lines, as well as for antifungal activity against four plant pathogenetic fungi (Alternaria solani, Botrytis cinerea, Fusarium oxysporum, and Valsa mali). Compound 2, a bisabolane-type sesquiterpenoid, was shown to possess excellent activity for control of B. cinerea with half-maximal inhibitory concentration (IC50) of 13.6 µg/mL, whereas the remaining investigated compounds showed either weak or no cytotoxic/antifungal activity in this study.

Difference of physiological characters in dark green islands and yellow leaf tissue of Cucumber mosaic virus (CMV)-infected Nicotiana tabacum leaves.

Dark green islands (DGIs) are a common symptom of plants systemically infected with the mosaic virus. DGIs are clusters of green leaf cells that are free of virus but surrounded by yellow leaf tissue that is full of virus particles. In Cucumber mosaic virus (CMV)-infected Nicotiana tabacum leaves, the respiration and photosynthesis capabilities of DGIs and yellow leaf tissues were measured. The results showed that the cyanide-resistant respiration was enhanced in yellow leaf tissue and the photosynthesis was declined, while in DGIs they were less affected. The activities of the oxygen-scavenging enzymes catalase (CAT), peroxidase (POD), and superoxide dismutase (SOD) in infected leaves were significantly higher than those in the healthy leaves, and the enzyme activities in DGIs were always lower than in the yellow leaf tissues. Reactive oxygen species (ROS) staining showed that the hydrogen peroxide content in yellow leaf tissues was apparently higher than that in DGIs, while the superoxide content was on the contrary. Formation of DGIs may be a strategy of the host plants resistance to the CMV infection.

Characterization and Absorption Kinetics of a Novel Multifunctional Nanoliposome Stabilized by Sea Cucumber Saponins Instead of Cholesterol.

Cholesterol was usually used to stabilize liposome, although there have been controversies on the relationship between dietary cholesterol and health. The present study aimed to prepare a novel multifunctional nanoliposomes stabilized by sea cucumber-derived saponins using ultrasound-assisted film dispersion method. A novel uniform liposome with a mass ratio of egg yolk lecithin/sea cucumber saponins at 75:25 was successfully prepared to encapsulate saponin, and the particle size was 164.8 ± 1.70 nm with a PDI value of 0.214 ± 0.022 and zeta potential of -15.97 ± 1.23 mV. The digestion and absorption results in vivo showed that the dietary saponins in liposome form could delay the peak time of saponins and prolong their residence time in the serum. Moreover, saponins were more easily converted into their corresponding metabolites after administration with saponins in the liposome form. The novel liposome as an efficient carrier with multiple functions had great potential in the development of functional food and biomedical applications.

Digestion, Absorption, and Metabolism Characteristics of EPA-Enriched Phosphoethanolamine Plasmalogens Based on Gastrointestinal Functions in Healthy Mice.

EPA-enriched phosphoethanolamine plasmalogens (EPA-pPE), widely present in marine creatures, is a unique glycerophospholipid with EPA at the sn-2 position of the glycerol backbone. EPA-pPE has been reported to exhibit numerous distinctive bioactivities. However, the digestion, absorption, and metabolism characteristics of EPA-pPE in vivo are not clear, which restrict the molecular mechanism analysis related to its distinctive activities. The aim of the present study was to illustrate the digestion, absorption, and metabolism characteristics of EPA-pPE by lipid analysis in serum, intestinal wall, and content after oral administration of EPA-pPE emulsion. Results showed the EPA percentage of total fatty acids in serum was increasing over time, with two peaks at 5 and 10 h by 1.89 ± 0.2 and 2.58 ± 0.27, respectively, and then fell from 1.89 ± 0.17 at 10 h to 1.35 ± 0.16 at 16 h. In small intestinal content, EPA-pPE was hydrolyzed to lyso-phospholipids and EPA by phospholipases A2 and the vinyl ether bond was retained at the sn-1 position. The released EPA could be quickly taken up into the enterocytes and enter circulation. The comparison of simulated digestion in vitro showed that the distinct digestion and absorption process of EPA-pPE was a unique phenomenon. EPA could be retained in serum at a high level for a substantial period of time, which suggested that EPA-pPE was not just a short-lived circulating molecule.