• <tr id="yyy80"></tr>
  • <sup id="yyy80"></sup>
  • <tfoot id="yyy80"><noscript id="yyy80"></noscript></tfoot>
  • 99热精品在线国产_美女午夜性视频免费_国产精品国产高清国产av_av欧美777_自拍偷自拍亚洲精品老妇_亚洲熟女精品中文字幕_www日本黄色视频网_国产精品野战在线观看 ?

    Mechanisms of protective effects of astaxanthin in nonalcoholic fatty liver disease

    2021-05-10 08:56:48LingJiaGaoYuQinZhuLiangXu
    Hepatoma Research 2021年4期

    Ling-Jia Gao, Yu-Qin Zhu, Liang Xu

    School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China.

    Abstract Nonalcoholic fatty liver disease is a major contributor to chronic liver disease worldwide, and 10%-20% of nonalcoholic fatty liver progresses to nonalcoholic steatohepatitis (NASH). Astaxanthin is a kind of natural carotenoid, mainly derived from microorganisms and marine organisms. Due to its special chemical structure,astaxanthin has strong antioxidant activity and has become one of the hotspots of marine natural product research.Considering the unique chemical properties of astaxanthin and the complex pathogenic mechanism of NASH,astaxanthin is regarded as a significant drug for the prevention and treatment of NASH. Thus, this review comprehensively describes the mechanisms and the utility of astaxanthin in the prevention and treatment of NASH from seven aspects: antioxidative stress, inhibition of inflammation and promotion of M2 macrophage polarization,improvement in mitochondrial oxidative respiration, regulation of lipid metabolism, amelioration of insulin resistance, suppression of fibrosis, and liver tumor formation. Collectively, the goal of this work is to provide a beneficial reference for the application value and development prospect of astaxanthin in NASH.

    Keywords: Nonalcoholic fatty liver disease, astaxanthin, fibrosis, insulin resistance, mitochondrial dysfunction,oxidative stress

    INTRODUCTION

    Nonalcoholic fatty liver disease (NAFLD) has become one of the most prevalent forms of chronic liver disease in most countries, and is frequently associated with obesity, metabolic syndrome, and type 2 diabetes[1]. NAFLD is characterized by the accumulation of triglyceride (TG) fats by more than 5% to 10% of the liver weight in the absence of superfluous alcohol consumption. Nonalcoholic steatohepatitis (NASH),an advanced form of NAFLD, is characterized by hepatocellular steatosis, lobular inflammation, and fibrosis, and may lead to liver cirrhosis and hepatocellular carcinoma[2-4]. According to global epidemiological research, the global prevalence of NAFLD is increasing year by year and reached approximately 25% by 2016[5-7]. Studies have shown that NAFLD is rapidly increasing as an indicator for liver transplantation, and its incidence in the United States is currently as high as one-third of the total population[8].

    For the pathogenesis of NASH, the widely accepted theory is the “second or multiple hits” hypothesis[9,10], as show as Figure 1. Although insulin resistance, enhanced oxidative stress followed by lipid peroxidation, and rising proinflammatory cytokine release are believed to be the major causes of progression to NASH[11,12], the concrete mechanisms remains obscure. Currently, NAFLD is considered to be an integral part of metabolic syndrome with insulin resistance as the central risk factor. Metabolic syndrome is often characterized by oxidative stress, a disturbance in the balance between the production of reactive oxygen species (ROS) and antioxidant defenses[13].

    Currently, several pharmacological agents, such as metformin, thiazolidinediones, and vitamin E have been tested as treatments for NASH in clinical trials[14-16]. However, these agents are generally insufficient to ameliorate liver inflammation and fibrosis, and have raised safety concerns. Therefore, a potential therapy with minimal adverse effects is eagerly awaiting. It has recently become clear that the effects of astaxanthin go beyond its antioxidant properties. Astaxanthin is a xanthophyll carotenoid found in marine organisms,including salmon, shrimp, crustaceans, and algae such as Haematococcus pluvialis[17,18]. Accumulating evidence suggests that astaxanthin could prevent or even reverse NASH by improving oxidative stress,inflammation, lipid metabolism, insulin resistance and fibrosis.

    The objective of this review is to summarize the bio-functions of astaxanthin in the prevention of NASH.

    SOURCE, SYNTHETIC AND BIOLOGICAL ACTIVITY OF ASTAXANTHIN

    Astaxanthin is a secondary carotenoid with a chemical structure of 3,3’-dihydroxy-4,4’-diketo-β, β’-carotene,which is known for its strong antioxidant activity. It is widely found in nature, such as leaves, flowers, fruits,feathers of flamingos, most fishes, members of the frog family, crustaceans, and the unicellular alga,Haematococcus pluvialis, which is the most ideal source of natural astaxanthin[17,19]. At present, astaxanthin is mainly obtained by the biological extraction of aquatic products and by artificial synthesis from carotene as the raw material. Because synthetic astaxanthin is expensive and less natural than natural astaxanthin in terms of chemical safety and biofunctionality, currently astaxanthin is almost always obtained by biological extraction for its use as a dietary supplement.

    At present, astaxanthin is widely used in the food industry as a dietary supplement in a growing number of countries. In 1987, the US Food and Drug Administration (FDA) approved astaxanthin as a feed additive for animal and fish feed; in 1999, the FDA authorized it as a dietary supplement for humans[20]. Astaxanthin is lipophilic and hydrophilic, it is absorbed by intestinal epithelial cells in the small intestine and then esterified. It is passively diffused and combined with fat molecules. The unesterified part is combined with chylomicrons and then passed through the lymphatic system for transport into the liver. Spiller and Dewell[21]used a randomized, controlled, double-blind approach to assess the safety of oral administration of astaxanthin (6 mg/d) in healthy individuals. There was no significant difference in blood pressure and various biochemical parameters at 4 and 8 weeks. Humans cannot synthesize astaxanthin, and the ingested astaxanthin cannot be converted to vitamin A; excessive intake of astaxanthin will thus not cause hypervitaminosis A[22,23]. Astaxanthin has physiological functions such as inhibiting tumorigenesis,protecting the nervous system, preventing diabetes and cardiovascular diseases[17,24-27], and it is widely used in various industries such as food, cosmetics, health care products, and aquaculture. Considering the biological characteristics of astaxanthin and the complex pathogenesis of NASH, it remains unknown whether astaxanthin can be used to treat NASH; the underlying mechanism of action also remains obscured.

    Figure 1. Multiple-hit hypothesis of the progression of NAFLD/NASH. Dietary habits, environmental, and genetic factors cause overweight or obesity and change the intestinal microbiome. This results in increased serum FFA and inflammatory factor (adipo-, cytoand/or chemokines) levels and eventually leads to insulin resistance. Furthermore, insulin resistance leads to an increase in DNL in the liver and increases the synthesis and accumulation of TG and toxic levels of fatty acids. Fat accumulation in the liver in the form of TG leads to liver steatosis (NAFL). Free cholesterol and other lipid metabolites cause mitochondrial dysfunction and subsequent oxidative stress, and ROS release and ER stress further activates UPR; which collectively lead to hepatic inflammation and fibrosis (NASH).NAFLD: Nonalcoholic fatty liver disease; NASH: nonalcoholic steatohepatitis; FFAs: free fatty acids; DNL: de novo lipogenesis; LPS:lipopolysaccharide; TNFα: tumor necrosis factor alpha: IL-6: interleukin-6; TG: triglycerides; ER: endoplasmic reticulum; UPR: unfolded protein response; ROS: reactive oxygen species.

    THE MECHANISM OF ASTAXANTHIN IN THE PREVENTION OF NASH

    Anti-oxidative stress effect

    As stated above, oxidative stress is one of the various factors that contribute to the “multiple hits” in the pathogenesis of NASH and is the main contributor of liver injury and disease progression in NAFLD.Indeed, several oxidative stress biomarkers that have been determined in clinical models of NAFLD include nitric oxide (NO), lipid peroxidation products [lipid peroxides, thiobarbituric acid reactive substances(TBARS), Hydroperoxides, 8-isoprostane and 4-Hydroxynonenal], protein oxidation products (protein carbonyl, nitrotyrosine), DNA oxidation product (8-OH-dG), and CYP2E1[28,29]. Additionally, two clinical studies have found that increases in oxidative stressin vivo,measured by urinary 8-iso-prostaglandin F2α(8-iso-PGF2α), which is derived from the non-enzymatic oxidation of arachidonic acid and serum levels of soluble NOX2-derived peptide (sNOX2-dp), is an indicator of NOX2 activation, a NADPH oxidase isoform involved in ROS generation[30,31].

    Oxidative stress damage is due to the imbalance of oxidation and anti-oxidation processes in the body that cause tissue injury induced by excessive production of free radicals, ROS and reactive nitrogen species(RNS). Excessive ROS can react with proteins, lipids and DNA through a chain reaction, thereby destroying homeostasis and causing tissue damage[32,33]. However, studies have shown that ROS can be eliminated from their oxidative activity by antioxidants such as carotenoids. Carotenoids contain polyene chains and longchain conjugated double bonds, which are responsible for antioxidant activities, acting by quenching singlet oxygen to terminate the free radical chain reaction in the organism[34,35]. Astaxanthin, one of the most prominent carotenoids with antioxidant activity, can penetrate the whole cell membrane, reduce membrane permeability, and limit the entry of peroxide promoters such as hydrogen peroxide and tert-butyl hydroperoxide into the cell[36,37]. Thus, oxidative damage to pivotal molecules in cells can be prevented.Astaxanthin scavenges oxygen free radicals and prevents lipid auto-oxidation with a capacity that is 6,000 times greater than that of vitamin C, 800 times that of coenzyme Q10, 550 times that of vitamin E, 200 times that of tea polyphenols, and 10 times that of beta carotene[17,38]; rightfully therefore known as a “super antioxidant”. Jorgensenet al.[39]found that astaxanthin is more effective than beta-carotene and zeaxanthin in preventing excessive oxidation of unsaturated fatty acid methyl esters. This conclusion has also been verified in various biofilm models, including phosphatidylcholine liposomes[40]and rat liver microsomes[37].

    Nakagawaet al.[41]reported that supplementation with astaxanthin (6 and 12 mg/d) in 30 healthy subjects decreased erythrocyte phospholipid hydroperoxide (PLOOH) levels and increased astaxanthin levels, 12 weeks after administration. An animal study showed that the concentration of catalase (CAT), superoxide dismutase (SOD) and peroxidase (POD) increased significantly in the plasma and hepatocytes of rats that were fed Haematococcus pluvialis[42]. In obese and overweight adults, astaxanthin supplementation (5 and 20 mg/d) dramatically reduced the level of biomarkers related to oxidative stress, including malondialdehyde (MDA) and isoprostane, and increased SOD and total antioxidant capacity (TAC). These findings indicate the strong antioxidant capacity of astaxanthinin vivo[43].

    Anti-inflammatory effect and enhancement in M2 macrophage polarization

    Given the strong link between inflammation and oxidative stress, it is not surprising that astaxanthin has been studied as an agent to attenuate inflammation.In vitro, astaxanthin has been shown to reduce proinflammatory markers in several cell lines, such as rat alveolar macrophages[44], U937 cells[45], RAW 264.7 cells[46], Thp-1 cells[24], proximal renal tubular epithelial cells[47], HUVECs[48], and human lymphocytes[49].

    Wanet al.[50]demonstrated that M2 macrophage/Kupffer cells promote apoptosis in M1 macrophage/Kupffer cells and inhibit NAFLD progression. Astaxanthin restrains M1 macrophage/Kupffer cells and increases M2 macrophage/Kupffer cells, reducing liver recruitment of CD4+and CD8+cells and inhibiting inflammatory responses in NAFLD[51]. Inflammatory factors aggravate the progression of NAFLD; however, astaxanthin reduces the levels of interleukin (IL)-6 and tumor necrosis factor (TNF) α in the liver through proliferator-activated receptor α (PPARα) to alleviate inflammation[52]. When NASH was induced by diet, administration of natural astaxanthin (0.02%, ≈ 20 mg/kg BW) reduced liver inflammation and insulin resistance in C57BL/6J mice[51]. Compared to vitamin E, astaxanthin was more effective in preventing and treating NASH in this animal model[51].

    Recently, the gut-liver axis has been shown to mediate the NASH progression[53]. Notably, liver lipopolysaccharide (LPS) is produced by intestinal microbiota, which were known to induce oxidative stress and inflammation. The LPS/toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling is critical for the activation of inflammatory pathways associated with NASH[54]. Lumenget al.[55]found that in primary macrophages and RAW 264.7 cells stimulated by LPS, astaxanthin significantly reduced the levels of NO, prostaglandin E2 (PGE2), TNFα, and IL-1β by inhibiting NF-κB activation. Macedoet al.[56]showed that astaxanthin can obviously reduce the production of proinflammatory cytokines, such as TNFα and IL-6, secreted by LPS-induced neutrophils and enhance the phagocytosis and bactericidal ability of neutrophils by inhibiting the production of O2-(superoxide anion radical) and H2O2.

    Improvement of mitochondrial respiratory chain

    Numerous studies have shown that excessive ROS can cause oxidative damage to mitochondria. In turn,damage to the mitochondrial respiratory chain complex I and III releases electrons to produce a large amount of ROS; approximately 90% of ROS in cells are produced from mitochondria. Superfluous ROS cause mitochondrial structural abnormalities and functional deficits, mainly manifested in decreased mitochondrial membrane potential, mitochondrial mutation, uncoupling of the mitochondrial respiratory chain, increased free radical production, and decreased adenosine triphosphate (ATP) production.Dysfunctional mitochondria trigger inflammatory cytokine production and often lead to the development of degenerative diseases, aging, metabolic diseases, cardiovascular diseases and so on.

    A growing body of studies has also involved astaxanthin in improving cellular mitochondrial oxidative respiratory chains to resist oxidative stress damage, and recent results hypothesize that astaxanthin has a“mitochondrial targeting” effect in cells. Fanet al.[57]verified that astaxanthin significantly attenuated homocysteine-induced cytotoxicity of H9C2 cells by inhibiting mitochondria-mediated apoptosis and blocked homocysteine-induced mitochondrial dysfunction by modulating the expression of the Bcl-2 family. Importantly, astaxanthin also significantly inhibits homocysteine-induced cardiotoxicityin vivoas well as improves angiogenesis. A similar study has shown that astaxanthin has the potential to reverse homocysteine-induced neurotoxicity and apoptosis by inhibiting mitochondrial dysfunction and ROSmediated oxidative damage and regulating the MAPK and AKT pathways[58]. After treatment of gastric epithelial cells with astaxanthin, Kimet al.[59]found that Helicobacter pylori-induced increases in ROS,mitochondrial dysfunction, NF-κB activation, and IL-8 expression were alleviated without affecting NADPH oxidase activity, indicating thereby that astaxanthin could prevent oxidative stress-mediated Helicobacter pylori infection that is associated with gastric inflammation Yuet al.[60]also found that astaxanthin can improve heat-induced skeletal muscle oxidative damage. In mouse C2C12 myoblasts exposed to heat stress at 43 ℃, astaxanthin lessened heat-induced ROS production in a concentrationdependent manner (1-20 μM), preventing mitochondrial disruption, depolarization and apoptotic cell death. Astaxanthin increases the protein expression of peroxisome proliferator-activated receptor γ coactivator-1β (PGC-1α) and mitochondrial transcription factor A (TFAM) at 37 ℃, and maintains mitochondrial tubular structure and a normal membrane potential (ΔΨm), i.e., maintainance of mitochondrial integrity and function. Data from Manoet al.[61]showed that astaxanthin inhibits oxidation and nitridation, which leads to apoptosis and lipid peroxidation of cytochrome c peroxidase, although its efficiency varies with membrane pH and lipid composition. It is hypothesized that astaxanthin is endowed with pH-dependent antioxidant/antiapoptotic properties in respiratory mitochondria. Astaxanthin and tocopherol nanoemulsions (NEs) were prepared using sodium caseinate (AS-AT/SC NEs) as a raw material to protect cells from ROS, oxidative stress, and mitochondrial membrane potential through mitochondriamediated apoptosis to prevent cell death, demonstrating therefore that apoptosis induced by AS-AT/SC NEs may be a potential method to destroy cancer cells[62]. Taken together, astaxanthin can ameliorate mitochondrial glutathione (GSH) activity, complex I activity, ATPase activity, mitochondrial membrane potential and fluidity by ROS, and excessively open the membrane permeability transition pore (MPTP)[63].

    Although an accurate discussion is lacking on the mechanisms by which mitochondria might assist in the prevention and treatment of NASH, the above studies suggest that mitochondrial function plays an indelible role in NASH.

    Lipid metabolism

    Jiaet al.[52]administered astaxanthin orally to C57BL/6J mice that were fed a high-fat diet for 8 weeks and found that astaxanthin could improve liver lipid accumulation and decrease liver TG levels. Astaxanthin was found to regulate PPAR levels. Activated PPARα increases liver fatty acid transport, metabolism, and oxidation levels; inhibits liver fat accumulation; induces hepatocyte autophagy; and cleaves lipid droplets through AMP-activated protein kinase/PGC-1α[64-66]. PPARα has become a key target for the treatment of NAFLD - activation of PPARγ regulates lipid synthesis-related gene expression and promotes fatty acid storage, and PPARγ overexpression induces hepatic lipid accumulation[67]. Astaxanthin activates PPARα,inhibits PPARγ expression, and reduces intrahepatic fat synthesis[63]. In addition, astaxanthin inhibits the AKT-mTOR pathway, which also causes autophagy of liver cells and breaks down lipid droplets stored in the liver[52]. Furthermore, astaxanthin reduces liver fatty acid synthesizing enzyme (FASN) mRNA levels and directly inhibitsde novosynthesis of fat[68].

    In vitroand clinical studies have shown that the continuous use of astaxanthin for 2 weeks can significantly prolong the oxidation time of low-density lipoprotein (LDL). Astaxanthin can inhibit the production of ox-LDL and the utilization of ox-LDL by the activation of macrophages along with the enhanced expression of PPARα. At the same time, it inhibits the expression of PPARγ and reduces the synthesis of fat in the liver.Augustiet al.[69]found that astaxanthin can significantly reduce oxidative stress damage and program lower blood lipid levels in rabbits with hypercholesterolemia. In patients with hypertriglyceridemia, serum TG levels of patients with long-term oral astaxanthin were significantly lower than those in the control group,while adiponectin and high-density lipoprotein (HDL) levels were significantly increased[70]. In obese and overweight people, oral astaxanthin lowers apolipoprotein B and LDL cholesterol levels and improves oxidative damage[43]. It has been reported that astaxanthin also reduces platelet aggregation and promote fibrinolytic activity in rats with hyperlipidemia induced by a high-fat diet. These positive effects are related to decreased serum lipid and lipoprotein levels, antioxidant production, and protection of endothelial cells[71].

    Amelioration of insulin resistance

    Insulin resistance is the major contributor to obesity, type 2 diabetes, and NAFLD. Insulin activates the tyrosine kinase activity of insulin receptor-beta (IRβ) subunits, which phosphorylates insulin receptor substrate, IRS, to activate the insulin metabolism pathway: IRS1-PI3K-AKT (insulin receptor substrate 1,phosphoinositide 3-kinase, serine/threonine kinase). When serine/threonine protein kinases, such as Jun Nterminal kinases (JNK) and mitogen-activated protein kinase 3 (ERK-1), inhibitors of nuclear factor kappa-B kinase (NF-κB) subunit beta (IKK-β), phosphorylate IRβ and IRS1, the IRS1-PI3K-AKT pathway is blocked and its activity decreases, and insulin resistance occurs accordingly[72,73]. The activation of JNK and NF-κB, stimulated by sustained endoplasmic reticulum (ER) stress also causes insulin resistance[74].Bhuvaneswariet al.[75,76]established a mouse model of type 2 diabetes induced by a high fructose-fat diet(HFFD) to study the effects of astaxanthin on hepatic insulin signaling and glucose metabolism.Astaxanthin intervention significantly improved insulin sensitivity in the HFFD group. This is because astaxanthin restores the insulin metabolic pathway by decreasing the activity of JNK and ERK-1 to ameliorate insulin resistance in the liver. Niet al.[51]constructed a diet-induced NASH mouse model that consisted of a high-fat, high cholesterol, and cholate diet (CL). In the fasting and fed states, glucose intolerance and hyperinsulinemia that accompanied the CL diet were significantly ameliorated by astaxanthin, and vitamin E treatment also reduced the plasma insulin levels to some extent. This result was related to the fact that astaxanthin-treated mice produced more insulin-stimulated phosphorylated IRβ and AKT than did control mice, while vitamin E had little effect on hepatic insulin signaling.

    Anti-fibrosis effect

    Hepatic fibrosis is a wound healing response characterized by excessive accumulation of extracellular matrix. Hepatic stellate cell (HSC) activation plays a key role in liver fibrosis[77]. Transforming growth factor beta 1 (TGF-β1) is the most effective profibrotic cytokine[78]. TGF-β1/Smad3 signaling regulates transcription of key genes in fibrosis, causing liver fibrosis. The imbalance in matrix metalloproteinases(MMPs) and MMP inhibitors (tissue inhibitor of MMPs, TIMPs) accelerates the progression of liver fibrosis, and TGF-β1 regulates the expression of MMPs and TIMPs. Yanget al.[79]confirmed that astaxanthin can reduce the expression of the TGF-β1-induced fibrosis genes α-SMA and Col1A1 and effectively inhibit fibrosis in LX-2 cells. The mechanism is that astaxanthin downregulates Smad3 phosphorylation and nuclear translocation induced by TGF-β1. Yanget al.[79]also observed that when activated primary HSCs were coincubated with astaxanthin, α-SMA mRNA and protein levels were significantly downregulated, indicating that astaxanthin can inhibit the early activation of resting HSCs.Shenet al.[80]studied the protective effect of astaxanthin on liver fibrosis induced by carbon tetrachloride(CCl4) and bile duct ligation. The results showed that astaxanthin effectively improved the pathological damage of liver fibrosis. Astaxanthin reduces the expression of TGF-β1 by downregulating nuclear NF-κB levels, maintains the balance between MMP2 and TIMP1, and inhibits the activation of HSCs and the formation of extracellular matrix (ECM). Hernandez-Geaet al.[81]reported that autophagic degradation of lipid droplets in HSCs provides energy for HSC activation, thereby aggravating the process of liver fibrosis.Astaxanthin alleviates HSC autophagy levels, reduces nutrient supply, and inhibits HSC activation. In addition, histone acetylation, as an epigenetic model, is involved in the activation of HSCs and the process of liver fibrosis[82]. Some studies have found that astaxanthin significantly suppresses the activation of HSCs by decreasing the expression of histone deacetylase 9 (HDAC9); HDAC3 and HDAC4 may also be involved in this process[74].

    Antitumor formation

    Hepatocellular carcinoma (HCC) is a malignant tumor with extremely high morbidity and mortality.Multiple signaling pathways, such as NF-κB p65, Wnt/beta-catenin, JAK/STAT, Hedgehog, Ras/MAPK and so on, are closely related to the development of liver cancer[83,84]. In the aflatoxin (AFB1)-induced liver cancer model, astaxanthin markedly reduced the number and size of liver cancer lesions. In-depth studies have found that astaxanthin significantly inhibits AFB1-induced single-strand DNA breaks and AFB1 binding to liver DNA and plasma albumin[85]. Tripathiet al.[86]found that astaxanthin inhibits cyclophosphamide-induced liver tumors in the early stage in rats. The Nrf2-ARE pathway is an endogenous antioxidant stress pathway that regulates the expression of SOD and DNA repair enzymes (e.g., OGG1,XRCC1, XPD, and XPG), which play an important role in tumorigenesis and progression[87,88]. Astaxanthin can inhibit the occurrence and development of liver cancer, which in turn, may be related to the activation of Nrf2-ARE pathway.

    Songet al.[89]confirmed that astaxanthin induces mitochondria-mediated apoptosis in the mouse liver cancer cell line CBRH-7919 by inhibiting the JAK/STAT3 pathway. In addition, astaxanthin inhibits liver tumorigenesis and may be involved in the regulation of NM23, which encodes a nucleoside diphosphate kinase. The upregulated expression of this protein is beneficial to the correct assembly of the cytoskeleton and the transmission of T protein signaling. Liet al.[90]confirmed that astaxanthin can prevent the proliferation of human hepatoma cells LM3 and SMMC-7721 and induce their apoptosis. The possible mechanism is that astaxanthin inhibits the NF-κB and Wnt/beta-catenin signaling pathways and regulates downstream the expression of the antiapoptotic protein, Bcl-2, and apoptosis-related gene, Bax; thereby promoting apoptosis of tumor cells. At the same time, astaxanthin decreases the phosphorylation of glycogen synthetase kinase-3 beta (GSK-3β) and inhibits tumor cell infiltration. Consistent with these findings, Shaoet al.[91]showed that astaxanthin can inhibit the proliferation of mouse hepatoma cell line H22 and arrest cells in the mitotic G2 phase.

    Figure 2. Mechanisms of the effects of astaxanthin on NASH. The strong antioxidant effect of astaxanthin can significantly inhibit oxidative stress, thereby reducing mitochondrial damage and endoplasmic reticulum stress, leading to a shift to M2 macrophage polarization and ultimately reversing liver steatosis, inflammation, and insulin resistance. Moreover, astaxanthin can reduce the activation of hepatic stellate cells to ameliorate hepatic fibrosis as a result of M1/M2 macrophage transformation. In addition,astaxanthin can inhibit the generation of hepatocyte tumors. Thus, astaxanthin prevents the development of NAFLD by inhibiting lipid accumulation, inflammation, and fibrosis in the liver. NAFLD: Nonalcoholic fatty liver disease; NASH: nonalcoholic steatohepatitis; KC:Kupffer cell; M1: proinflammatory macrophages; M2: anti-inflammatory macrophages; HSC: hepatic stellate cells; HCC: hepatocellular carcinoma.

    The increase inde novofat synthesis is a common feature of many malignant tumors. FASN is expressed in a variety of malignant tumors, including liver cancer[92,93], and astaxanthin downregulates liver FASN mRNA levels to restrain liver tumorigenesis[94]. In addition, adipocytokines, another key regulator of the fat synthesis pathway, play an important role in repressing the proliferation of human liver tumor cells and inducing apoptosis. Astaxanthin observably inhibits liver tumorigenesis in obese mice by increasing serum adipocytokine levels[95].

    CONCLUSION

    Astaxanthin has been recognized as a new food resource and is expected to have good application prospects in health food and dietary supplements. The prevalence of NASH continues to persist globally, and its complex and diverse pathogenesis makes it difficult to diagnose and treat. Currently, there are no FDAapproved standard drug regimens in the guidelines for management of NASH. At present, great progress has been made in researching the antioxidant activity of astaxanthin. A large number of studies have demonstrated that astaxanthin can prevent or treat NASH through various mechanisms [Figure 2]. Most studies on the influence of astaxanthin on NASH remain at the cellular and animal experiment level.However, the presented research in this work on the prevention and treatment of NASH by astaxanthin indicates that there is broad potential and hope for the application of astaxanthin in NASH. As a futuristic goal, we still need large-scale clinical trials to verify the actual effects of astaxanthin on the human body and provide a theoretical basis to continually explore the beneficial effects of astaxanthin antioxidant activity on the human body.

    DECLARATIONS

    Authors’ contributions

    Contributed to the drafting and writing of the manuscript: Gao LJ, Zhu YQ, Xu L

    Availability of data and materials

    Not applicable.

    Financial support and sponsorship

    This study was supported by Xinmiao Talents Program of Zhejiang Province granted to L.G (2019R413070)and Wenzhou Municipal Science and Technology Bureau granted to L.X. (Y20190049).

    Conflicts of interest

    All authors declared that there are no conflicts of interest.

    Ethical approval and consent to participate

    Not applicable.

    Consent for publication

    Not applicable.

    Copyright

    ? The Author(s) 2021.

    热99久久久久精品小说推荐| 亚洲少妇的诱惑av| 精品少妇久久久久久888优播| 麻豆乱淫一区二区| 黑人欧美特级aaaaaa片| 日本猛色少妇xxxxx猛交久久| 欧美bdsm另类| 日韩中字成人| 国产97色在线日韩免费| 国产激情久久老熟女| 黑人猛操日本美女一级片| 亚洲国产av新网站| 国产探花极品一区二区| 国产深夜福利视频在线观看| 精品一区二区三卡| 天堂中文最新版在线下载| 久久久精品国产亚洲av高清涩受| 久久97久久精品| 水蜜桃什么品种好| 成年动漫av网址| 亚洲第一区二区三区不卡| 菩萨蛮人人尽说江南好唐韦庄| 国产av国产精品国产| 激情视频va一区二区三区| 午夜福利一区二区在线看| 国产成人精品无人区| 少妇的丰满在线观看| 9191精品国产免费久久| 三上悠亚av全集在线观看| 欧美人与善性xxx| 日产精品乱码卡一卡2卡三| 亚洲欧洲日产国产| 午夜激情av网站| 亚洲国产看品久久| 国产福利在线免费观看视频| 永久免费av网站大全| 国产成人91sexporn| 91精品伊人久久大香线蕉| 欧美 日韩 精品 国产| 中文字幕人妻丝袜一区二区 | 亚洲第一区二区三区不卡| 国产成人免费观看mmmm| 午夜91福利影院| av线在线观看网站| 亚洲成人av在线免费| 人人妻人人澡人人看| 黄色毛片三级朝国网站| 久久久久久人妻| 人人妻人人爽人人添夜夜欢视频| 久久精品亚洲av国产电影网| 精品第一国产精品| 亚洲精品在线美女| 亚洲在久久综合| 国产精品成人在线| 欧美日韩视频高清一区二区三区二| 人妻系列 视频| 热99久久久久精品小说推荐| av在线观看视频网站免费| 国产精品一区二区在线不卡| 日韩中文字幕欧美一区二区 | 国产又爽黄色视频| 亚洲一码二码三码区别大吗| www.精华液| 久久久久精品性色| 考比视频在线观看| 亚洲精品久久久久久婷婷小说| 久久ye,这里只有精品| 在线免费观看不下载黄p国产| 80岁老熟妇乱子伦牲交| 免费人妻精品一区二区三区视频| 观看美女的网站| 国产精品久久久久久久久免| 五月开心婷婷网| 国产国语露脸激情在线看| 午夜福利视频精品| 涩涩av久久男人的天堂| 日本免费在线观看一区| xxx大片免费视频| 中文乱码字字幕精品一区二区三区| 日本欧美视频一区| 男女啪啪激烈高潮av片| 青春草亚洲视频在线观看| 青春草国产在线视频| 久久av网站| 欧美精品一区二区免费开放| 啦啦啦在线免费观看视频4| 纯流量卡能插随身wifi吗| 看十八女毛片水多多多| 国产97色在线日韩免费| a级毛片黄视频| 80岁老熟妇乱子伦牲交| 中文欧美无线码| 欧美日韩视频高清一区二区三区二| 亚洲国产欧美日韩在线播放| 午夜福利在线免费观看网站| 一本—道久久a久久精品蜜桃钙片| 2021少妇久久久久久久久久久| 国产xxxxx性猛交| 交换朋友夫妻互换小说| 男女国产视频网站| 超碰97精品在线观看| 成年人免费黄色播放视频| 国产极品粉嫩免费观看在线| 咕卡用的链子| 美女中出高潮动态图| 久久久亚洲精品成人影院| 国产亚洲最大av| 国产精品一二三区在线看| 欧美日本中文国产一区发布| 日本vs欧美在线观看视频| 午夜福利影视在线免费观看| 亚洲国产毛片av蜜桃av| 老鸭窝网址在线观看| 成人漫画全彩无遮挡| 香蕉精品网在线| 色94色欧美一区二区| 日韩一卡2卡3卡4卡2021年| 性色avwww在线观看| 国产色婷婷99| 国产精品国产三级专区第一集| 我的亚洲天堂| 亚洲图色成人| 国产福利在线免费观看视频| 青春草亚洲视频在线观看| 欧美 日韩 精品 国产| 国产高清不卡午夜福利| 午夜激情久久久久久久| 麻豆精品久久久久久蜜桃| 国产精品二区激情视频| 亚洲欧洲国产日韩| 2021少妇久久久久久久久久久| 80岁老熟妇乱子伦牲交| 观看av在线不卡| 精品国产国语对白av| 乱人伦中国视频| 亚洲第一区二区三区不卡| www.熟女人妻精品国产| 欧美 日韩 精品 国产| 人体艺术视频欧美日本| 国产精品 欧美亚洲| 精品国产超薄肉色丝袜足j| 亚洲成av片中文字幕在线观看 | 亚洲一级一片aⅴ在线观看| 久久久精品94久久精品| xxxhd国产人妻xxx| 热re99久久精品国产66热6| 妹子高潮喷水视频| 日韩在线高清观看一区二区三区| 精品福利永久在线观看| 99香蕉大伊视频| 有码 亚洲区| av国产久精品久网站免费入址| 少妇精品久久久久久久| 最新的欧美精品一区二区| 啦啦啦中文免费视频观看日本| 九九爱精品视频在线观看| 免费观看在线日韩| 中国国产av一级| 女的被弄到高潮叫床怎么办| 中文字幕人妻丝袜制服| 久久ye,这里只有精品| 亚洲精品国产av蜜桃| 永久网站在线| 成人18禁高潮啪啪吃奶动态图| 18禁动态无遮挡网站| 久久人妻熟女aⅴ| 丰满乱子伦码专区| 亚洲精品国产av蜜桃| 久久精品国产亚洲av高清一级| 免费人妻精品一区二区三区视频| 一级毛片电影观看| 国产爽快片一区二区三区| 中文字幕另类日韩欧美亚洲嫩草| 国产亚洲最大av| 久久久久久人妻| 亚洲精品aⅴ在线观看| 久久综合国产亚洲精品| 男女午夜视频在线观看| av在线观看视频网站免费| 日本爱情动作片www.在线观看| 亚洲精品中文字幕在线视频| 香蕉丝袜av| 一级毛片电影观看| 老熟女久久久| 一级片免费观看大全| 日韩成人av中文字幕在线观看| 丝袜喷水一区| 黄片无遮挡物在线观看| 丰满少妇做爰视频| 另类亚洲欧美激情| 久久精品久久久久久噜噜老黄| 不卡av一区二区三区| 久久久欧美国产精品| 免费在线观看黄色视频的| 欧美国产精品va在线观看不卡| 18禁国产床啪视频网站| 色吧在线观看| 妹子高潮喷水视频| 亚洲国产精品一区二区三区在线| 日韩成人av中文字幕在线观看| 少妇精品久久久久久久| 日本色播在线视频| 欧美国产精品va在线观看不卡| 亚洲,欧美,日韩| 桃花免费在线播放| 一区二区三区激情视频| 国产有黄有色有爽视频| 久久综合国产亚洲精品| 国产免费又黄又爽又色| 最黄视频免费看| 成年人午夜在线观看视频| h视频一区二区三区| 哪个播放器可以免费观看大片| 亚洲欧美清纯卡通| 91精品三级在线观看| 国产精品人妻久久久影院| 免费看av在线观看网站| 国产福利在线免费观看视频| 美女福利国产在线| 热99久久久久精品小说推荐| 国产成人免费观看mmmm| 超碰97精品在线观看| 制服丝袜香蕉在线| 国精品久久久久久国模美| 青春草视频在线免费观看| 日本色播在线视频| 美女国产高潮福利片在线看| 伦理电影大哥的女人| 午夜久久久在线观看| 999久久久国产精品视频| 寂寞人妻少妇视频99o| 亚洲精品久久午夜乱码| 80岁老熟妇乱子伦牲交| 亚洲伊人久久精品综合| 性色av一级| 寂寞人妻少妇视频99o| 午夜免费鲁丝| 久热这里只有精品99| 亚洲欧美成人综合另类久久久| 国产精品免费视频内射| 丝袜美腿诱惑在线| av在线播放精品| 精品国产一区二区三区四区第35| 哪个播放器可以免费观看大片| 老司机亚洲免费影院| 日韩,欧美,国产一区二区三区| 国产成人精品婷婷| 黑人巨大精品欧美一区二区蜜桃| 街头女战士在线观看网站| 我要看黄色一级片免费的| 十八禁网站网址无遮挡| √禁漫天堂资源中文www| 黑人巨大精品欧美一区二区蜜桃| 国产极品天堂在线| 中文字幕精品免费在线观看视频| 久久久久精品人妻al黑| 欧美精品av麻豆av| 国产又爽黄色视频| 亚洲国产av影院在线观看| 亚洲欧美日韩另类电影网站| 夫妻性生交免费视频一级片| 亚洲情色 制服丝袜| 天天影视国产精品| 欧美日韩精品成人综合77777| 午夜激情av网站| 99国产综合亚洲精品| 国产精品一区二区在线不卡| 国产精品香港三级国产av潘金莲 | 国产免费福利视频在线观看| 少妇猛男粗大的猛烈进出视频| 日韩在线高清观看一区二区三区| 啦啦啦在线观看免费高清www| 久久精品久久久久久久性| 成年美女黄网站色视频大全免费| 大片免费播放器 马上看| 欧美老熟妇乱子伦牲交| √禁漫天堂资源中文www| 自线自在国产av| 免费人妻精品一区二区三区视频| a 毛片基地| 午夜福利在线免费观看网站| 啦啦啦在线免费观看视频4| 久久精品aⅴ一区二区三区四区 | 性色av一级| 男女下面插进去视频免费观看| 国产成人a∨麻豆精品| 亚洲人成网站在线观看播放| 777米奇影视久久| 亚洲精品一区蜜桃| 日韩伦理黄色片| 啦啦啦啦在线视频资源| 电影成人av| 午夜老司机福利剧场| 久久鲁丝午夜福利片| 国产视频首页在线观看| 午夜福利乱码中文字幕| 亚洲综合色网址| av在线app专区| 欧美bdsm另类| 国产精品久久久久久久久免| 黄片无遮挡物在线观看| 亚洲精品第二区| 制服丝袜香蕉在线| 亚洲欧美清纯卡通| 波野结衣二区三区在线| 久久韩国三级中文字幕| 欧美激情极品国产一区二区三区| 亚洲精品久久午夜乱码| 亚洲久久久国产精品| 国产视频首页在线观看| 80岁老熟妇乱子伦牲交| 国产一区亚洲一区在线观看| 日韩中文字幕欧美一区二区 | 国产亚洲午夜精品一区二区久久| 亚洲欧美精品综合一区二区三区 | 制服丝袜香蕉在线| 一级毛片电影观看| 蜜桃国产av成人99| 欧美日韩综合久久久久久| 久久久国产一区二区| 青春草国产在线视频| 性高湖久久久久久久久免费观看| 久久久久视频综合| www日本在线高清视频| 一区二区日韩欧美中文字幕| 亚洲色图 男人天堂 中文字幕| 午夜老司机福利剧场| 国产午夜精品一二区理论片| 欧美激情高清一区二区三区 | av免费在线看不卡| 在线免费观看不下载黄p国产| 国产福利在线免费观看视频| 色婷婷久久久亚洲欧美| 满18在线观看网站| 国产片特级美女逼逼视频| 国产熟女欧美一区二区| 最近手机中文字幕大全| 欧美日韩一区二区视频在线观看视频在线| 欧美日韩国产mv在线观看视频| 岛国毛片在线播放| 91精品国产国语对白视频| 亚洲久久久国产精品| 9色porny在线观看| 中文字幕人妻丝袜一区二区 | 婷婷成人精品国产| 国产熟女午夜一区二区三区| 久久久久久免费高清国产稀缺| 免费高清在线观看视频在线观看| 精品少妇一区二区三区视频日本电影 | 18禁动态无遮挡网站| 成人黄色视频免费在线看| 日韩一区二区三区影片| 视频在线观看一区二区三区| 青春草国产在线视频| 汤姆久久久久久久影院中文字幕| 三级国产精品片| 熟女电影av网| 日韩欧美精品免费久久| 国产成人精品福利久久| 日日摸夜夜添夜夜爱| 成年人免费黄色播放视频| 91在线精品国自产拍蜜月| 不卡视频在线观看欧美| 高清不卡的av网站| 波野结衣二区三区在线| 99久久综合免费| 午夜福利在线免费观看网站| 日韩免费高清中文字幕av| 99国产综合亚洲精品| 丰满少妇做爰视频| 日本-黄色视频高清免费观看| 春色校园在线视频观看| 大话2 男鬼变身卡| 国产成人aa在线观看| 日韩av不卡免费在线播放| 一二三四在线观看免费中文在| 男女啪啪激烈高潮av片| 建设人人有责人人尽责人人享有的| 丝袜人妻中文字幕| 久久久久久免费高清国产稀缺| 91aial.com中文字幕在线观看| 免费看av在线观看网站| 久久久久精品久久久久真实原创| www.自偷自拍.com| 国产精品亚洲av一区麻豆 | 亚洲av日韩在线播放| 久久久久网色| 男女啪啪激烈高潮av片| 亚洲精品在线美女| 26uuu在线亚洲综合色| 精品99又大又爽又粗少妇毛片| 国产欧美日韩综合在线一区二区| 精品人妻一区二区三区麻豆| 亚洲综合色网址| 成年动漫av网址| 免费av中文字幕在线| 热99久久久久精品小说推荐| 校园人妻丝袜中文字幕| 亚洲av电影在线进入| 咕卡用的链子| 午夜福利网站1000一区二区三区| 久久久久国产精品人妻一区二区| 国产极品天堂在线| 女的被弄到高潮叫床怎么办| 久久久久久伊人网av| 国产精品久久久av美女十八| 欧美少妇被猛烈插入视频| 亚洲精品一二三| 我的亚洲天堂| 亚洲成色77777| 久久精品国产综合久久久| 中文字幕另类日韩欧美亚洲嫩草| 欧美日韩av久久| 美女大奶头黄色视频| 免费黄色在线免费观看| av免费观看日本| 亚洲美女搞黄在线观看| 十分钟在线观看高清视频www| 国产成人精品一,二区| 国产精品三级大全| 日韩在线高清观看一区二区三区| 久久综合国产亚洲精品| 两个人免费观看高清视频| 日韩三级伦理在线观看| 超碰97精品在线观看| 日本免费在线观看一区| 国产片内射在线| 18禁观看日本| 99香蕉大伊视频| 黄色 视频免费看| 最新的欧美精品一区二区| 啦啦啦视频在线资源免费观看| 亚洲国产看品久久| 菩萨蛮人人尽说江南好唐韦庄| 亚洲精品在线美女| 久久久久久久久久久久大奶| 国产在视频线精品| 国产精品.久久久| 美女xxoo啪啪120秒动态图| 国产成人精品一,二区| 国产精品秋霞免费鲁丝片| 韩国高清视频一区二区三区| 最近手机中文字幕大全| 免费观看在线日韩| 九色亚洲精品在线播放| 国产精品成人在线| 国产深夜福利视频在线观看| 国产成人精品婷婷| 深夜精品福利| 久久午夜福利片| 黄频高清免费视频| 一级a爱视频在线免费观看| 黄片无遮挡物在线观看| 亚洲国产精品国产精品| 一边亲一边摸免费视频| 91精品三级在线观看| 亚洲婷婷狠狠爱综合网| 边亲边吃奶的免费视频| 亚洲精品在线美女| 国产成人91sexporn| 美女午夜性视频免费| 国产亚洲最大av| 久久鲁丝午夜福利片| 美国免费a级毛片| 满18在线观看网站| 亚洲精品在线美女| 亚洲av男天堂| av视频免费观看在线观看| 黄色怎么调成土黄色| 久久女婷五月综合色啪小说| 9热在线视频观看99| 街头女战士在线观看网站| 久久精品国产亚洲av天美| av又黄又爽大尺度在线免费看| 热99久久久久精品小说推荐| 国产1区2区3区精品| 日本-黄色视频高清免费观看| 侵犯人妻中文字幕一二三四区| 国产一区二区三区av在线| 精品亚洲乱码少妇综合久久| 欧美国产精品一级二级三级| 岛国毛片在线播放| 五月天丁香电影| 18在线观看网站| 天天躁夜夜躁狠狠躁躁| 精品午夜福利在线看| 亚洲第一青青草原| 9191精品国产免费久久| 日韩av不卡免费在线播放| 国产精品蜜桃在线观看| 成人国语在线视频| 欧美激情 高清一区二区三区| 在线观看免费高清a一片| 亚洲欧美一区二区三区黑人 | 超色免费av| 丝瓜视频免费看黄片| 啦啦啦在线观看免费高清www| 亚洲男人天堂网一区| 久久精品国产综合久久久| 精品人妻偷拍中文字幕| 精品99又大又爽又粗少妇毛片| xxx大片免费视频| 免费在线观看完整版高清| 好男人视频免费观看在线| 伊人亚洲综合成人网| 欧美 日韩 精品 国产| 日韩三级伦理在线观看| 伦精品一区二区三区| 人妻人人澡人人爽人人| av在线观看视频网站免费| 亚洲精品一区蜜桃| 伦理电影免费视频| 午夜福利在线免费观看网站| 少妇人妻精品综合一区二区| 精品一区二区三区四区五区乱码 | 97精品久久久久久久久久精品| 国产欧美日韩综合在线一区二区| 青春草视频在线免费观看| 亚洲精品久久午夜乱码| 寂寞人妻少妇视频99o| 男女边摸边吃奶| 在线亚洲精品国产二区图片欧美| 大片电影免费在线观看免费| 在线天堂中文资源库| 色婷婷久久久亚洲欧美| 美女主播在线视频| 成年女人在线观看亚洲视频| 啦啦啦中文免费视频观看日本| 亚洲欧美一区二区三区黑人 | 亚洲伊人久久精品综合| kizo精华| 久久国产亚洲av麻豆专区| videosex国产| 美国免费a级毛片| 亚洲精品久久久久久婷婷小说| 久久精品国产亚洲av天美| 一级毛片 在线播放| 国产精品久久久av美女十八| 亚洲欧洲精品一区二区精品久久久 | 人妻 亚洲 视频| 久久韩国三级中文字幕| 麻豆av在线久日| 99久久人妻综合| 精品一区在线观看国产| 人体艺术视频欧美日本| 在线观看www视频免费| 国产精品亚洲av一区麻豆 | 日本色播在线视频| 亚洲三级黄色毛片| 日日爽夜夜爽网站| 日韩人妻精品一区2区三区| 韩国精品一区二区三区| 亚洲欧洲精品一区二区精品久久久 | 国产成人一区二区在线| 亚洲四区av| 婷婷色综合大香蕉| 精品一品国产午夜福利视频| 嫩草影院入口| 亚洲av中文av极速乱| 国产在线一区二区三区精| 在线观看国产h片| 亚洲成人av在线免费| 丰满饥渴人妻一区二区三| 最近最新中文字幕免费大全7| 亚洲,欧美,日韩| 亚洲精品日本国产第一区| 欧美人与性动交α欧美精品济南到 | 亚洲一码二码三码区别大吗| 午夜精品国产一区二区电影| 亚洲欧洲日产国产| 国产高清不卡午夜福利| 热re99久久精品国产66热6| 中文精品一卡2卡3卡4更新| 亚洲精品美女久久av网站| 人妻少妇偷人精品九色| 菩萨蛮人人尽说江南好唐韦庄| 亚洲第一青青草原| 国产精品熟女久久久久浪| 99热国产这里只有精品6| 精品人妻在线不人妻| 久久精品国产综合久久久| 街头女战士在线观看网站| 亚洲三级黄色毛片| 亚洲成人手机| 久久99蜜桃精品久久| 免费少妇av软件| 国产免费视频播放在线视频| 一级,二级,三级黄色视频| 丁香六月天网| 久久青草综合色| 亚洲激情五月婷婷啪啪| 波多野结衣av一区二区av| 一区二区三区四区激情视频| 日韩av在线免费看完整版不卡| 精品亚洲乱码少妇综合久久| 在线观看美女被高潮喷水网站| 天天操日日干夜夜撸| 精品亚洲乱码少妇综合久久| 国产成人av激情在线播放| 精品福利永久在线观看| 97在线人人人人妻| 亚洲精品久久午夜乱码| 一级,二级,三级黄色视频| 免费黄频网站在线观看国产| 91在线精品国自产拍蜜月| 日韩av在线免费看完整版不卡| av在线老鸭窝| 啦啦啦在线免费观看视频4| 亚洲av国产av综合av卡| 国产精品麻豆人妻色哟哟久久| 国产成人免费无遮挡视频| 超色免费av| 成年女人在线观看亚洲视频| 99九九在线精品视频| av免费观看日本|