The synergistic effect of sea cucumber saponins and caffeine on preventing obesity in high-fat diet-fed mice by extending the action duration of caffeine.

BACKGROUND: Sea cucumber saponins (SCSs) exhibit a unique structure and high bioactivities and might have specialized implications on caffeine metabolic process by altering the activity of N-demethylation enzyme CYP1A2. The present study aimed to clarify the effects of SCS on caffeine metabolism in vivo and in vitro, as well as the synergistic anti-obesity effect of SCS and caffeine on high-fat diet-induced obese mice. RESULTS: Results found that SCS administration significantly postponed the elimination rate of caffeine and its metabolites in vivo, and further study found CYP1A2-mediated caffeine metabolism was remarkably inhibited in a dose-dependent manner in vitro. The synergistic effect of the SCS and caffeine combination could decrease the total weight of white adipose tissue by 52% compared with high-fat diet-treated group. CONCLUSION: SCS could prolong caffeine action time, and the combination of the two substances exhibited joint action on high-fat diet-induced obese mice. These findings might provide a basis for the development of functional foods and potential application using the combination of SCS and caffeine. © 2022 Society of Chemical Industry.

Phosphatidylglucose alleviates atherosclerosis by increasing cholesterol alienation to bile acids and cholesterol efflux in ApoE-/- mice.

BACKGROUND: Phosphatidylcholine (PC) is considered to be the major dietary source for choline, which is associated with atherosclerosis progress. Thus, phosphatidylglucose (PG) was prepared by enzymatic modification of PC to investigate the effects on atherosclerosis in apolipoprotein E deficient (ApoE-/- ) mice, as well as to investigate its dose-response relationship. RESULTS: The results showed that dietary PG significantly decreased the atherosclerotic lesion area in a dose-dependent manner. Further studies found that intervention with a 0.8 g kg-1 and 2 g kg-1 PG diet for 4 months significantly decreased free cholesterol level and thus reduced total cholesterol levels in serum. The results of cholesterol distribution among lipoproteins showed that dietary PG significantly decreased low-density lipoprotein levels in ApoE-/- mice. In addition, only administration of high-dose PG significantly reduced total cholesterol levels in liver tissues by 31.2%. Furthermore, mice treated with high-dose PG had an expanded bile acid pool and increased the ratio of conjugated bile acids to unconjugated bile acids in the liver, serum and gallbladder by increasing hepatic gene expression of primary and conjugated bile acid synthesis. Additionally, low-dose and high-dose PG significantly increased total fecal sterols by 20.8% and 11.9%, respectively, by increasing sitosterol and ethylcoprostanol levels. CONCLUSION: These results indicate that PG alleviated atherosclerosis in a dose-dependent manner by increasing cholesterol alienation to bile acids and cholesterol efflux. © 2023 Society of Chemical Industry.

A Comparative Study of the Anti-Obesity Effects of Dietary Sea Cucumber Saponins and Energy Restriction in Response to Weight Loss and Weight Regain in Mice.

Dietary supplementation of sea cucumber saponins and calorie restriction have been proved to be effective in alleviating obesity, but the differences of anti-obesity effects between sea cucumber saponins and energy restriction during weight loss and weight regain are still unknown. In the present study, high-fat-induced obesity mice were randomly divided into three groups, including a high-fat diet group (HF), an energy restriction by 40% group (HF-L), and a sea cucumber saponins group (HF-S), to compare the effects of dietary sea cucumber saponins and energy restriction on the weight, glucose, and lipid metabolism of obese mice during weight loss and weight regain. The results showed that dietary 0.06% sea cucumber saponins and limiting energy intake by 40% had the same weight loss effect. Interestingly, sea cucumber saponins could alleviate impaired glucose tolerance and insulin resistance caused by obesity. In addition, the inhibited SREBP-1c mediated lipogenesis might lead to the alleviation of weight regain after resuming the high-fat diet even when sea cucumber saponins were no longer supplemented. In contrast, limiting energy intake tended to promote lipid synthesis in the liver and white adipose tissue after restoring a high-fat diet, and inflammation was also induced. The findings indicated that sea cucumber saponins could replace calorie restriction to prevent obesity and might be used as a functional food or drug to resist obesity and related diseases caused by obesity.

EPA-Enriched Phospholipids Alleviate Renal Interstitial Fibrosis in Spontaneously Hypertensive Rats by Regulating TGF-ß Signaling Pathways.

Hypertensive nephropathy is a chronic kidney disease caused by hypertension. Eicosapentaenoic acid (EPA) has been reported to possess an antihypertensive effect, and our previous study suggested that EPA-enriched phospholipid (EPA-PL) had more significant bioactivities compared with traditional EPA. However, the effect of dietary EPA-PL on hypertensive nephropathy has not been studied. The current study was designed to examine the protection of EPA-PL against kidney damage in spontaneously hypertensive rats (SHRs). Treatment with EPA-PL for three weeks significantly reduced blood pressure through regulating the renin-angiotensin system in SHRs. Moreover, dietary EPA-PL distinctly alleviated kidney dysfunction in SHRs, evidenced by reduced plasma creatinine, blood urea nitrogen, and 24 h proteinuria. Histology results revealed that treatment of SHRs with EPA-PL alleviated renal injury and reduced tubulointerstitial fibrosis. Further mechanistic studies indicated that dietary EPA-PL remarkably inhibited the activation of TGF-ß and Smad 3, elevated the phosphorylation level of PI3K/AKT, suppressed the activation of NF-κB, reduced the expression of pro-inflammatory cytokines, including IL-1ß and IL-6, and repressed the oxidative stress and the mitochondria-mediated apoptotic signaling pathway in the kidney. These results indicate that EPA-PL has potential value in the prevention and alleviation of hypertensive nephropathy.

Rhodium(III)-catalyzed C4-amidation of indole-oximes with dioxazolones via C-H activation.

A novel method for the Rh(iii)-catalyzed oxime-directed C-H amidation of indoles with dioxazolones has been developed. This strategy provides an exclusive site selectivity and the directing group can be easily removed. This transformation features a wide substrate scope, good functional group tolerance and excellent yields, and may serve as a significant tool to construct structurally diverse indole derivatives for the screening of potential pharmaceuticals in the future.

Eicosapentaenoic acid-enriched phospholipids alleviate glucose and lipid metabolism in spontaneously hypertensive rats with CD36 mutation: a precise nutrition strategy.

Previous studies have found that eicosapentaenoic acid-enriched phospholipids (EPA-PLs) alleviated glucose and lipid metabolism, which was accompanied by an increase of cluster of differentiation 36 (CD36). However, the effects of EPA-PLs on glucose and lipid metabolism in the case of CD36 mutation are unclear. Thus, spontaneously hypertensive rats/NCrl (SHR) were used as a CD36 mutation model to determine the effects of dietary 2% EPA-PLs for 4 weeks on glucose and lipid metabolism. The results showed that the intervention of EPA-PLs significantly alleviated the abnormal increase of serum free fatty acid levels and glycerol levels in SHRs. Moreover, the administration of EPA-PLs decreased the triglyceride levels and cholesterol levels by 31.1% and 37.9%, respectively, in the liver. Dietary EPA-PLs had no effect on epididymal fat weight, but EPA-PLs inhibited adipocyte hypertrophy in SHRs. Further mechanistic research found that EPA-PL pretreatment significantly reduced triacylglycerol catabolism and increased fatty acid ß-oxidation. Additionally, the administration of EPA-PLs decreased the area under the curve of the intraperitoneal glucose tolerance test and fasting serum insulin levels by activating the IRS/PI3K/AKT signaling pathway. Furthermore, EPA-PL pretreatment significantly increased the CD36 gene expression in the liver tissues, adipose tissues and muscle tissues even in the case of CD36 mutation. These results indicated that EPA-PLs alleviate glucose and lipid metabolism in the case of CD36 mutation, which provides a precise nutrition strategy for people with CD36 mutation.

Free astaxanthin-rich diets enhanced astaxanthin accumulation in egg yolks compared to esterified astaxanthin-rich diets.

As an oxycarotenoid with strong antioxidant properties, astaxanthin can considerably boost pigmentation and improve the nutritional value of eggs. The purpose of this study was to elucidate the comparative effects of different chemical structures of astaxanthin including free astaxanthin, monoester-enriched astaxanthin and diester-enriched astaxanthin on the nutritional enhancement of eggs within 20 days. The results showed that supplementation of free astaxanthin to laying hens was more effective in accumulating astaxanthin in egg yolks than supplementation with esterified astaxanthin. The retention rate of free astaxanthin was approximately 12.0 % at the plateau phase in egg yolk, while that of monoester-enriched and diester-enriched astaxanthin were 4.0 % and 2.5 %, respectively. Free astaxanthin possessed a high retention rate and pigmentation effect compared with esterified astaxanthin, which might provide a basis for astaxanthin enhancement in eggs and potential application in nutritional functional foods.

N-3 PUFA Deficiency from Early Life to Adulthood Exacerbated Susceptibility to Reactive Oxygen Species-Induced Testicular Dysfunction in Adult Mice.

Homeostasis of reactive oxygen species is required to maintain sperm maturation and capacitation. Docosahexaenoic acid (DHA) is accumulated in testicles and spermatozoa and has the ability to manipulate the redox status. The effects of dietary n-3 polyunsaturated fatty acid (n-3 PUFA) deficiency from early life to adulthood on the physiological and functional properties of males under the redox imbalance of testicular tissue deserve attention. The consecutive injection of hydrogen peroxide (H2O2) and tert-butyl hydroperoxide (t-BHP) for 15 days to induce oxidative stress in testicular tissue was used to elucidate the consequences of testicular n-3 PUFA deficiency. The results indicated that reactive oxygen species treatment in adult male mice with DHA deficiency in the testis could reduce spermatogenesis and disrupt sex hormone production, as well as trigger testicular lipid peroxidation and tissue damage. N-3 PUFA deficiency from early life to adulthood resulted in higher susceptibility to testicular dysfunction in the germinal function of supplying germ cells and the endocrine role of secreting hormones through the mechanism of aggravating mitochondria-mediated apoptosis and destruction of blood testicular barrier under oxidative stress, which might provide a basis for humans to reduce susceptibility to chronic disease and maintain reproductive health in adulthood through dietary interventions of n-3 PUFAs.

DHA-Enriched Phospholipids Exhibit Anti-Depressant Effects by Immune and Neuroendocrine Regulation in Mice: A Study on Dose- and Structure-Activity Relationship.

SCOPE: It has been reported that eicosapentaenoic acid (EPA), especially EPA-enriched phospholipids (EPA-PL), significantly ameliorates depression-like behavior in mice, while the corresponding effect of docosahexaenoic acid (DHA) is weak. However, it is still unclear whether the limited effect of DHA on alleviating depression is remedied by dose and chemical structure adjustment to DHA-PL. METHODS AND RESULTS: A mouse model with depression is established by chronic unpredictable mild stress (CUMS) coupled with lipopolysaccharide (LPS) challenge to simulate the infection-triggered immune perturbation during chronic stress, and the effects of dietary 0.2% EPA-PL, 0.2% DHA-PL, 0.6% DHA-PL, and 0.6% DHA-enriched ethyl ester (DHA-EE) are comparatively investigated. The results demonstrate that dietary 0.6% DHA-PL, instead of 0.2% DHA-PL and 0.6% DHA-EE, significantly rescues the depression-like behavior with similar effects to 0.2% EPA-PL. Further studies reveal that dietary DHA-PL regulates immune dysregulation, inhibits neuroinflammation by NLRP3 inflammasome, and further improves monoamine systems and the hypothalamic-pituitary-adrenal (HPA) axis. CONCLUSION: The limited effect of DHA on depression is remedied by chemical structure adjustment to DHA-PL and three-fold dose. The present findings provide a potential novel candidate or targeted dietary patterns to prevent and treat depression.

Taurine Alleviates Trimethylamine N-Oxide-Induced Atherosclerosis by Regulating Bile Acid Metabolism in ApoE-/- Mice.

Trimethylamine N-oxide (TMAO) widely exists in seafood and is associated with the atherosclerosis progress, but dietary seafood reduced the cardiovascular risk. This intimates that there may be some ingredients in seafood to offset the cardiovascular risk caused by TMAO. Taurine is a marker ingredient in seafood. Thus, this study determined the influences of taurine on TMAO-induced atherosclerosis in apolipoprotein-E-deficient mice. The results showed that dietary taurine significantly reduced the TMAO-induced atherosclerotic lesion area. Further studies found that taurine increased the hepatic- and serum-conjugated bile acid/unconjugated bile acid ratio via increasing hepatic gene expression of conjugated bile acid synthesis. Meanwhile, taurine changed TMAO-induced abnormal bile acid profiles in the gallbladder. Moreover, taurine increased bile acid deconjugation by enhancing the genera Ruminiclostridium level and increased excretion of fecal neutral sterols. Additionally, taurine attenuated inflammation in the serum and artery. These results indicate that taurine alleviated TMAO-induced atherosclerosis via regulating bile acid metabolism.

Comparative Analyses of EPA-Phosphatidylcholine, EPA-Lysophosphatidylcholine, and DHA-Lysophosphatidylcholine on DHA and EPA Repletion in n-3 PUFA-Deficient Mice.

Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) play an important role in maintaining the physiological functions of tissues, and the beneficial effects of DHA/EPA in phospholipid forms have been widely reported. Although lysophosphatidylcholine (LPC) is considered to be the preferred form of DHA supplementation for the brain, the kinetics of DHA and EPA recovery and corresponding changes of n-6 docosapentaenoic acid (DPA) and arachidonic acid (AA) levels in different phospholipid molecules and different tissues after administration of EPA in phosphatidylcholine (PC) and LPC forms and DHA in the LPC form are not clear. Here, we measured the total fatty acids in tissues and fatty acid composition of different phospholipid molecules after gavage administration of equal molar amounts of EPA/DHA in mice with n-3 polyunsaturated fatty acid (PUFA) deficiency induced by maternal dietary deprivation of n-3 PUFA during pregnancy and lactation. The results showed that dietary supplementation with EPA-PC, EPA-LPC, and DHA-LPC exhibited different priorities for EPA or DHA accretion and supplementation efficiency curves in different tissues during the developing period. EPA-PC exhibited a more optimal efficacy in DHA and EPA repletion in serum and hepatic total fatty acids. In terms of DHA recovery in the brain, EPA-LPC and DHA-LPC showed great effects. Meanwhile, the DHA level in total fatty acids and major fractions of phospholipids (PC, PE, and PI + PS) in the heart and bone marrow with the supplementation of DHA-LPC displayed a relatively considerable increase compared with that of EPA supplementation groups. The study provides a reference for the time course of DHA or EPA recovery in phospholipid molecular species in different tissues after the supplementation of EPA-PC, EPA-LPC, and DHA-LPC.

Antarctic krill oil exhibited synergistic effects with nobiletin and theanine in ameliorating memory and cognitive deficiency in SAMP8 mice: Applying the perspective of the sea-land combination to retard brain aging.

The complex pathogenesis of Alzheimer's disease (AD) leads to a limited therapeutic effect; therefore, the combination of multiple bioactive ingredients may be more effective in improving AD due to synergistic effects. Based on the perspective of the sea-land combination, the effects of sea-derived Antarctic krill oil (AKO) combined with land-derived nobiletin (Nob) and L-theanine (The) on memory loss and cognitive deficiency were studied in senescence-accelerated prone 8 mice (SAMP8). The results demonstrated that AKO combined with The significantly increased the number of platform crossings in the Morris water maze test by 1.6-fold, and AKO combined with Nob significantly increased the preference index in a novel object recognition test. AKO exhibited synergistic effects with Nob and The in ameliorating recognition memory and spatial memory deficiency in SAMP8 mice, respectively. Further research of the mechanism indicated that AKO exhibited synergistic effects with Nob in suppressing ß-amyloid (Aß) aggregation, neurofibrillary tangles, and apoptosis and neuroinflammation, while the synergistic effects of AKO and The involved in synaptic plasticity and anti-neuroinflammation, which revealed that the combination was complex, not a mechanical addition. These findings revealed that the sea-land combination may be an effective strategy to treat and alleviate AD.

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.

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.

Dietary Supplementation with Exogenous Sea-Cucumber-Derived Ceramides and Glucosylceramides Alleviates Insulin Resistance in High-Fructose-Diet-Fed Rats by Upregulating the IRS/PI3K/Akt Signaling Pathway.

Endogenous ceramide is considered to be associated with the progress of insulin resistance. However, the effects of dietary exogenous glucosylceramides and ceramides on insulin resistance are unclear. A model of fructose-induced male Sprague Dawley rats was used to compare the effects of sea-cucumber-derived glucosylceramides and ceramides on insulin resistance. Both glucosylceramides and ceramides significantly improved glucose tolerance, reduced the concentrations of serum glucose and glycosylated hemoglobin, and alleviated the accompanied hypertension. Ceramides significantly enhanced glycogen levels in skeletal muscle, whereas glucosylceramides significantly increased the hepatic glycogen levels. Moreover, glucosylceramides alleviated insulin resistance by inhibiting gluconeogenesis, promoting glycogen synthesis and insulin signal transduction in the liver; meanwhile, ceramides were mainly due to the promotion of glycogen synthesis and insulin signal transduction in skeletal muscle. Additionally, glucosylceramides and ceramides effectively attenuated inflammation in adipose tissue. These results indicate that glucosylceramides and ceramides have potential value in the prevention and alleviation of insulin resistance.

The enrichment of eggs with docosahexaenoic acid and eicosapentaenoic acid through supplementation of the laying hen diet.

The enrichment and transformation of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) enriched phospholipids for eggs deserve attention. The aim of the present study was to elucidate the comparative effects of DHA and EPA enriched phospholipids and triacylglycerols on egg fortification by determining the fatty acid composition of egg yolk after intervention with fish oil (15 g/kg) and krill oil (15 and 30 g/kg) for three consecutive weeks. The results indicated that laying hens could incorporate over 300 mg DHA and EPA into one egg. Greater retention efficiency of DHA and EPA in eggs was observed in fish oil supplementation compared with krill oil at equivalent dietary levels. DHA and EPA were prone to locate at the sn-2 position of phosphatidylcholine. Consequently, fish oil possessed high DHA content and conversion rate, and krill oil could raise the proportion of DHA-containing phospholipids in eggs.