Publications by authors named "Hao-Hao Shi"

12 Publications

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Dietary n-3 PUFA Deficiency Increases Vulnerability to Scopolamine-Induced Cognitive Impairment in Male C57BL/6 Mice.

J Nutr 2021 May 12. Epub 2021 May 12.

College of Food Science and Engineering, Ocean University of China, Qingdao, Shandong, China.

Background: DHA (22:6n-3), a long-chain n-3 PUFA, is essential for normal brain development and function. Our previous study demonstrated that DHA significantly improves scopolamine-induced dementia. However, there are no reports on the relation between n-3 PUFA deficiency and scopolamine-induced cognitive impairment.

Objectives: The aim of this study was to evaluate whether n-3 PUFA deficiency increases vulnerability to scopolamine-induced cognitive impairment.

Methods: Male and female C57BL/6 mice were mated and fed an n-3 PUFA-adequate [containing 2.88% α-linolenic acid (ALA; 18:3n-3)] or -deficient (containing 0.09% ALA) diet for 2 consecutive generations. The corresponding second-generation male offspring were kept on the same diet as their mothers after weaning, and were randomly assigned to 2 subgroups at 7 wk of age, in which they were intraperitoneally injected with saline [fed n-3 PUFA-adequate (Con) or -deficient (Def) diet] or scopolamine [5 mg/kg body weight; fed n-3 PUFA-adequate (Sco) or -deficient (Def + Sco) diet] once per day for 7 d before killing. Behavioral performance was analyzed using the Morris Water Maze test. Fatty acid composition, protein expression, and indicators of cholinergic and oxidative stress in the brain were measured.

Results: The Def group showed lower brain DHA (-63.7%, P ≤ 0.01) and higher n-6 PUFA (+65.5%, P ≤ 0.05) concentrations than the Con group. The Def + Sco group and the Sco group showed poorer spatial learning and memory (escape latency on the sixth day: +60.3% and +36.8%; platform crossings: -43.9% and -28.2%, respectively) and more obvious cholinergic dysfunction (acetylcholine: -47.6% and -27.7%, respectively), oxidative stress (glutathione peroxidase: -64.2% and -32.5%, respectively), apoptosis [B-cell lymphoma 2 (BCL2)-associated X protein/BCL2: +230.8% and +153.8%; phosphorylated P38/P38: +232% and +130%, phosphorylated c-Jun N-terminal kinase (JNK)/JNK: +104.5% and +58.8%, respectively], neuroinflammation (IL-1β: +317.6% and +95%, respectively), and neurodevelopmental delay (brain-derived neurotrophic factor: -54.4% and -7.25%, respectively) than their corresponding saline-treated controls.

Conclusions: Dietary n-3 PUFA deficiency significantly decreases brain DHA concentrations and increases vulnerability to scopolamine-induced cognitive impairment in C57BL/6 male mice.
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http://dx.doi.org/10.1093/jn/nxab116DOI Listing
May 2021

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

Food Funct 2021 Jun;12(11):4887-4896

College of Food Science and Engineering, Ocean University of China, Qingdao, 266003, Shandong, China.

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.
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http://dx.doi.org/10.1039/d0fo03266bDOI Listing
June 2021

A comparative study of the effects of phosphatidylserine rich in DHA and EPA on Aβ-induced Alzheimer's disease using cell models.

Food Funct 2021 May 20;12(10):4411-4423. Epub 2021 Apr 20.

College of Food Science and Engineering, Ocean University of China, Qingdao, 266003, Shandong, China.

Alzheimer's disease (AD) is an age-dependent, irreversible neurodegenerative disease, and one of the pathological features is amyloid-β (Aβ) deposition. Previous studies have shown that phosphatidylserine (PS) enriched with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) exhibited significant effects in preventing and alleviating the progress of AD. However, no studies have focused on the differences in the preventive effects on AD between EPA-PS and DHA-PS. Here, the effects of EPA-PS and DHA-PS on Aβ production, Aβ-induced neurotoxicity and Aβ clearance have been studied. The results show that DHA-PS significantly reduced Aβ production in CHO-APP/PS1 cells compared to EPA-PS. Moreover, both EPA-PS and DHA-PS significantly protected the primary hippocampal neurons against Aβ-induced toxicity by inhibiting the mitochondrial-dependent apoptotic pathway and phosphorylation of JNK and p38. Compared to DHA-PS, EPA-PS administration significantly improved the Aβ phagocytic capacity of BV2 cells. In addition, EPA-PS and DHA-PS significantly promoted the neurite outgrowth of primary hippocampal neurons. These findings might provide dietary guidance for the prevention of AD as well as a reference for the development of related functional foods.
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http://dx.doi.org/10.1039/d1fo00286dDOI Listing
May 2021

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.

J Agric Food Chem 2021 Feb 9. Epub 2021 Feb 9.

College of Food Science and Engineering, Ocean University of China, Qingdao, Shandong 266003, People's Republic of China.

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.
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http://dx.doi.org/10.1021/acs.jafc.0c06831DOI Listing
February 2021

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

Food Chem 2021 Jun 29;346:128958. Epub 2020 Dec 29.

College of Food Science and Engineering, Ocean University of China, Qingdao 266003, Shandong, PR China; Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao 266237, Shandong Province, PR China. Electronic address:

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.
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http://dx.doi.org/10.1016/j.foodchem.2020.128958DOI Listing
June 2021

Sea cucumbers-derived sterol sulfate alleviates insulin resistance and inflammation in high-fat-high-fructose diet-induced obese mice.

Pharmacol Res 2020 10 8;160:105191. Epub 2020 Sep 8.

College of Food Science and Engineering, Ocean University of China, Qingdao, 266003, Shandong, China; Laboratory of Marine Drugs & Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao, 266237, Shandong Province, China. Electronic address:

Sea cucumbers are widely consumed in traditional medicine and food. Sea cucumbers-derived sulfated sterol exhibits a sulfate group at C-3 position, which is different from phytosterol with a hydroxyl group. However, the effect of sterol sulfate on metabolic syndrome remains unknown. The purpose of the present study is to investigate the alleviation of sterol sulfate on high-fat-high-fructose diet (HFFD)-induced insulin resistance and inflammation. After 2 weeks feeding with HFFD, male C57BL/6J mice were continuously fed with HFFD plus 0.4 % (w/w) sterol sulfate or phytosterol for 6 weeks. The OGTT was carried out at 7 weeks. At the end of the experimental period, the changes of glycogen, circulating glucose, insulin, pro-inflammatory cytokine and adiponectin were measured. H&E staining was used to observe the morphological changes in adipose tissue. Furthermore, the underlying molecular mechanisms were investigated. Dietary sterol sulfate was superior to phytosterol in reducing body weight gain, adipocyte hypertrophy, and levels of circulating glucose and insulin, as well as increasing the glycogen content of tissues. Furthermore, sterol sulfate ameliorated insulin resistance mainly due to the inhibition of gluconeogenesis, the promotion of glycogen synthesis and GLUT4 translocation by activating PI3K/Akt signaling pathway. Additionally, sterol sulfate effectively attenuated inflammation by increasing serum adiponectin and reducing pro-inflammatory cytokine release. Sterol sulfate exhibited a more significant effect than phytosterol in alleviating HFFD -induced insulin resistance and inflammation, which might be closely related to the sulfate group. The results might provide insights into the prevention and alleviation of metabolic syndrome.
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http://dx.doi.org/10.1016/j.phrs.2020.105191DOI Listing
October 2020

Docosahexaenoic acid-acylated astaxanthin ester exhibits superior performance over non-esterified astaxanthin in preventing behavioral deficits coupled with apoptosis in MPTP-induced mice with Parkinson's disease.

Food Funct 2020 Sep;11(9):8038-8050

College of Food Science and Engineering, Ocean University of China, No. 5 Yushan Road, Qingdao 266003, P. R. China. and Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao 266237, Shandong Province, P. R. China.

Non-esterified astaxanthin (AST) has been reported to exhibit protective effects from Parkinson's disease (PD). Notably, DHA-acylated astaxanthin ester (DHA-AST) is widely distributed in the seafood. However, whether DHA-AST has an effect on PD, and the differences between DHA-AST, non-esterified AST and the combination of non-esterified AST (AST) with DHA (DHA + AST) is unclear. In the present study, mice with PD, induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), were employed to investigate the effects of DHA-AST, AST and DHA + AST on Parkinson's disease. The rotarod test results showed that DHA-AST significantly suppressed the PD development in MPTP-induced mice, and was better than the effects of AST and DHA + AST. Further mechanistic studies indicated that all three astaxanthin supplements could inhibit oxidative stress in the brain. It was noted that DHA-AST had the best ability to suppress the apoptosis of dopaminergic neurons via the mitochondria-mediated pathway and JNK and P38 MAPK pathway in the brain among the three treated groups. DHA-AST was superior to AST in preventing behavioral deficits coupled with apoptosis rather than oxidative stress, and might provide a valuable reference for the prevention and treatment of neurodegenerative diseases.
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http://dx.doi.org/10.1039/d0fo01176bDOI Listing
September 2020

Eicosapentaenoic Acid-Enriched Phosphoethanolamine Plasmalogens Alleviated Atherosclerosis by Remodeling Gut Microbiota to Regulate Bile Acid Metabolism in LDLR Mice.

J Agric Food Chem 2020 May 4;68(19):5339-5348. Epub 2020 May 4.

College of Food Science and Engineering, Ocean University of China, No. 5 Yushan Road, Qingdao 266003, Shandong Province, P. R. China.

Eicosapentaenoic acid (EPA)-enriched phosphoethanolamine plasmalogens (EPA-PlsEtns) might be retained in the intestine rich in gut microbiota for a long time after treatment. It reminded us that EPA-PlsEtns might affect intestinal microbiota composition and its metabolites, which have been identified as a contributing factor in the development of cardiovascular diseases. In the present study, EPA-PlsEtn administration for 8 weeks significantly reduced the atherosclerotic lesion area in low-density lipoprotein receptor deficient (LDLR) mice. Notably, the serum total cholesterol and low-density lipoprotein cholesterol levels were significantly reduced by 33.6 and 38.2%, respectively, by EPA-PlsEtns instead of EPA in the form of ethyl ester (EPA-EE) treatment compared with the model group. EPA-PlsEtn administration also increased total neutral sterol and bile acids in feces by 92 and 39%, respectively, rather than EPA-EE. Mechanistically, EPA-PlsEtns might affect the abundance of gut microbiota contributing to the alteration of bile acid profiles, which might further accelerate bile acid synthesis via increasing cholesterol 7 α-hydroxylase expression induced by the inhibition of farnesoid X receptor activation.
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http://dx.doi.org/10.1021/acs.jafc.9b08296DOI Listing
May 2020

A pilot study on the effects of DHA/EPA-enriched phospholipids on aerobic and anaerobic exercises in mice.

Food Funct 2020 Feb;11(2):1441-1454

College of Food Science and Engineering, Ocean University of China, No. 5 Yushan Road, Qingdao 266003, P. R. China.

The beneficial effects of nonpolar DHA/EPA in triacylglycerol (TG) and ethyl ester (EE) forms as well as terrestrial phospholipids on physical fatigue have been widely reported. However, the results involving the effects were inconsistent, and the reason might be that the differences in physical fatigue induced by aerobic and anaerobic exercises were usually ignored. In addition, it has been reported the significant improvement of DHA/EPA esterified to phospholipids (DHA/EPA-PLs) on many fields but not physical fatigue. Therefore, the effects of DHA/EPA-PLs on physical fatigue induced by aerobic and anaerobic exercises were evaluated and compared with those of l-carnitine and astaxanthin using swimming and running exhaustion tests in mice, respectively. The results indicated that DHA/EPA-PLs and l-carnitine have significant effects on the performance of aerobic exercise, while astaxanthin had remarkable effects on the performance of anaerobic exercise. The possible underlying mechanisms indicated that DHA/EPA-PLs significantly promoted the carbohydrate and lipid metabolism as well as the mitochondrial respiratory chain and tricarboxylic acid cycle in muscles. The study presented a potential novel candidate or targeted dietary patterns for alleviating physical fatigue.
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http://dx.doi.org/10.1039/c9fo02489aDOI Listing
February 2020

Eicosapentaenoic acid in the form of phospholipids exerts superior anti-atherosclerosis effects to its triglyceride form in ApoE mice.

Food Funct 2019 Jul;10(7):4177-4188

College of Food Science and Engineering, Ocean University of China, Qingdao, 266003, Shandong, China.

Dietary eicosapentaenoic acid (EPA), a main component of fish oil, has been proved to reduce the risk of cardiovascular disease. The purpose of this study was to investigate whether the anti-atherosclerosis effect of fish oil enriched with EPA partially relied on its chemical groups at the sn-3 position. Male ApoE-/- mice were divided into three groups and were fed a high-fat diet (Model) or a high-fat diet containing EPA incorporated into phospholipids (EPA-PL) or triglycerides (EPA-TG), respectively. Compared with the model group, a decrease in the area of atherosclerosis lesions at the aorta was observed in both EPA-treated groups, in which EPA-PL was superior to EPA-TG. Notably, EPA-PL exhibited lower serum and hepatic lipid levels than the model group, whereas EPA-TG only reduced the hepatic triglyceride level. Interestingly, only EPA-PL treatment regulated the expression of genes involved in cholesterol metabolism. In addition, EPA-PL and EPA-TG suppressed the inflammation markers in the aorta and circulation. In conclusion, EPA-PL was superior to EPA-TG in reducing lesion progression by modulating the hepatic lipid metabolism, as well as decreasing the inflammation in the artery wall and circulatory system, which might be attributed to their structural differences at the sn-3 position.
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http://dx.doi.org/10.1039/c9fo00868cDOI Listing
July 2019

Synergistic effect of sea cucumber saponins and EPA-enriched phospholipids on insulin resistance in high-fat diet-induced obese mice.

Food Funct 2019 Jul;10(7):3955-3964

College of Food Science and Engineering, Ocean University of China, No. 5 Yushan Road, Qingdao 266003, P. R. China. and Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, P. R. China.

Sea cucumber saponins (SCS) exhibit a significant effect on ameliorating glucose and lipid disorders by inhibiting fatty acid biosynthesis; however, high cytotoxicity and hemolytic activity limit their application. Eicosapentaenoic acid-enriched phospholipids (EPA-PL) significantly ameliorate insulin resistance and elevate the level of hepatic lipolysis, which may have a synergistic effect with SCS in alleviating obesity-related insulin resistance via multiple mechanisms. In the present study, high-fat diet-induced male C57BL/6J mice with obesity-related insulin resistance were used to evaluate the synergistic effect of SCS and EPA-PL on alleviating the insulin resistance. Results show that the combination of SCS and EPA-PL at a half dose exhibited a significant improvement on glucose intolerance and systematic insulin sensitivity than SCS or EPA-PL alone. Moreover, the half dose-combination remarkably inhibited the macrophage infiltration (F4/80) to white adipose tissue (WAT) and significantly down-regulated the level of MCP1, TNF-α and IL-6 compared with SCS and EPA-PL alone. Consequently, the combined administration not only decreased hepatic gluconeogenesis and increased hepatic glycogen synthesis (P < 0.05), but also stimulated the glucose uptake in WAT and muscle (P < 0.05). Nevertheless, neither SCS or EPA-PL alone exhibited any effect on the glucose uptake. The combination of SCS and EPA-PL contributed to a synergistic effect on alleviating the obesity-related insulin resistance due to the amelioration of an inflammation-centric peripheral insulin response.
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http://dx.doi.org/10.1039/c9fo01147aDOI Listing
July 2019

DHA-PC protects kidneys against cisplatin-induced toxicity and its underlying mechanisms in mice.

Food Funct 2019 Mar;10(3):1571-1581

College of Food Science and Engineering, Ocean University of China, No. 5 Yushan Road, Qingdao, Shandong Province 266003, PR China.

Cisplatin is an effective chemotherapeutic agent used in the treatment of various cancers. However, its use is usually complicated by nephrotoxic side effects, which limit its clinical application. Interestingly, DHA supplementation has been found to exhibit anticancer activity without any side effects. It is noted that DHA-PC has been applied in the treatment of kidney diseases. Our aim in the current study was to investigate whether DHA-PC treatment could alleviate cisplatin-induced nephrotoxicity using a Balb/c mice model. Our results showed that DHA-PC could significantly prolong the survival time, while the traditional DHA had no remarkable changes. In addition, short supplements of DHA-PC alleviated the cisplatin-induced kidney dysfunction, such as increased levels of blood urea nitrogen and creatinine. DHA-PC could protect the kidneys against cisplatin-induced toxicity, which might be attributed to the sirtuin 1 activation and the inhibition of oxidative stress and apoptosis. These findings suggest that DHA-PC might be a new dietary strategy for the treatment of nephrotoxicity.
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http://dx.doi.org/10.1039/c8fo02386gDOI Listing
March 2019