• <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.

    丰满人妻一区二区三区视频av| 欧美性猛交╳xxx乱大交人| 免费观看性生交大片5| 能在线免费观看的黄片| 99久久精品一区二区三区| 亚洲色图av天堂| 亚洲自拍偷在线| 亚洲精品国产成人久久av| 欧美日韩国产mv在线观看视频 | 日本一二三区视频观看| 极品少妇高潮喷水抽搐| 免费av不卡在线播放| 日本色播在线视频| 欧美性猛交╳xxx乱大交人| 国产麻豆成人av免费视频| 久久久久久久亚洲中文字幕| 国内精品美女久久久久久| 国产成人91sexporn| 一区二区三区四区激情视频| 亚洲精品国产av蜜桃| 人人妻人人看人人澡| 午夜福利网站1000一区二区三区| 国产成人精品婷婷| 在线 av 中文字幕| 可以在线观看毛片的网站| 日本免费在线观看一区| 日韩制服骚丝袜av| 一区二区三区免费毛片| 观看免费一级毛片| 麻豆久久精品国产亚洲av| av免费在线看不卡| 国产精品久久视频播放| 国产大屁股一区二区在线视频| 成年版毛片免费区| 亚洲av男天堂| 国产亚洲av嫩草精品影院| 亚洲国产精品国产精品| 肉色欧美久久久久久久蜜桃 | 丰满少妇做爰视频| 国产亚洲一区二区精品| 亚洲精品第二区| 国产精品国产三级专区第一集| 免费无遮挡裸体视频| 国产一级毛片七仙女欲春2| 神马国产精品三级电影在线观看| 日本黄大片高清| 最近最新中文字幕免费大全7| 嫩草影院入口| 中文字幕免费在线视频6| 不卡视频在线观看欧美| 国产真实伦视频高清在线观看| 中国国产av一级| 97精品久久久久久久久久精品| 亚洲丝袜综合中文字幕| 一区二区三区高清视频在线| 亚洲国产欧美人成| a级毛色黄片| 国产又色又爽无遮挡免| 少妇人妻一区二区三区视频| 视频中文字幕在线观看| 干丝袜人妻中文字幕| 中文资源天堂在线| 汤姆久久久久久久影院中文字幕 | 国产单亲对白刺激| 久久久久免费精品人妻一区二区| 国产精品无大码| 青青草视频在线视频观看| 国产乱来视频区| 亚洲精品一二三| 国产永久视频网站| 深爱激情五月婷婷| 中文字幕免费在线视频6| 国产精品.久久久| 男女下面进入的视频免费午夜| 成人午夜高清在线视频| videos熟女内射| 亚洲成人av在线免费| 精品一区二区免费观看| 国产精品嫩草影院av在线观看| 免费观看精品视频网站| 男人舔奶头视频| 舔av片在线| 久久久久性生活片| 免费看光身美女| 99热这里只有是精品在线观看| 午夜精品一区二区三区免费看| 国产免费一级a男人的天堂| 亚洲av福利一区| 一本一本综合久久| 久久久久久久久中文| 午夜福利在线在线| 久久精品久久精品一区二区三区| 日本三级黄在线观看| 三级男女做爰猛烈吃奶摸视频| 欧美最新免费一区二区三区| 精品一区二区免费观看| 91精品伊人久久大香线蕉| 乱系列少妇在线播放| 精品久久久久久久人妻蜜臀av| 男女啪啪激烈高潮av片| 久久99热这里只频精品6学生| 国产v大片淫在线免费观看| 久久久久久久久久成人| 亚洲国产av新网站| 国产老妇伦熟女老妇高清| 亚洲丝袜综合中文字幕| 日本午夜av视频| 亚洲国产精品成人综合色| 蜜桃久久精品国产亚洲av| 欧美最新免费一区二区三区| 夫妻午夜视频| 国产69精品久久久久777片| 少妇熟女aⅴ在线视频| 欧美bdsm另类| 亚洲欧美清纯卡通| 美女被艹到高潮喷水动态| 日韩精品青青久久久久久| 乱人视频在线观看| 欧美成人精品欧美一级黄| 亚洲av二区三区四区| 久久久久久久久大av| 久久久色成人| 日韩,欧美,国产一区二区三区| 国产一区二区在线观看日韩| 在线 av 中文字幕| 熟妇人妻久久中文字幕3abv| 日韩大片免费观看网站| 亚洲国产精品成人久久小说| 麻豆成人av视频| 看非洲黑人一级黄片| 天天躁日日操中文字幕| 欧美潮喷喷水| av免费观看日本| 大片免费播放器 马上看| 亚洲在线自拍视频| av播播在线观看一区| 久久精品久久精品一区二区三区| 免费观看精品视频网站| eeuss影院久久| 一区二区三区免费毛片| 亚洲精华国产精华液的使用体验| av国产免费在线观看| 性插视频无遮挡在线免费观看| 亚洲av成人精品一区久久| 亚洲精品自拍成人| 性插视频无遮挡在线免费观看| 99热这里只有是精品50| 国产黄频视频在线观看| 禁无遮挡网站| 日韩国内少妇激情av| 日日撸夜夜添| 国产精品国产三级国产专区5o| 国产精品一区二区三区四区免费观看| 日韩大片免费观看网站| 欧美3d第一页| 欧美最新免费一区二区三区| or卡值多少钱| av在线老鸭窝| 欧美日韩在线观看h| 91精品伊人久久大香线蕉| 免费少妇av软件| av在线观看视频网站免费| 亚洲aⅴ乱码一区二区在线播放| 十八禁国产超污无遮挡网站| av播播在线观看一区| av卡一久久| 免费少妇av软件| 国产黄频视频在线观看| 久久99蜜桃精品久久| 一本—道久久a久久精品蜜桃钙片 精品乱码久久久久久99久播 | 日韩亚洲欧美综合| av在线亚洲专区| 久久精品夜夜夜夜夜久久蜜豆| 免费观看的影片在线观看| 久久久精品免费免费高清| 亚洲国产精品sss在线观看| 一区二区三区免费毛片| 人妻一区二区av| 欧美日韩亚洲高清精品| 人妻夜夜爽99麻豆av| 久久综合国产亚洲精品| 亚洲人成网站高清观看| 五月伊人婷婷丁香| 亚洲国产色片| 三级经典国产精品| 中文精品一卡2卡3卡4更新| 免费在线观看成人毛片| 三级经典国产精品| 成人漫画全彩无遮挡| 欧美高清性xxxxhd video| 身体一侧抽搐| 丝袜美腿在线中文| 久久久久久久久中文| 亚洲美女视频黄频| 99热这里只有是精品在线观看| 最近中文字幕2019免费版| 男女边吃奶边做爰视频| 尤物成人国产欧美一区二区三区| 2021天堂中文幕一二区在线观| 18禁在线无遮挡免费观看视频| av专区在线播放| 亚洲精品成人久久久久久| 亚洲av免费高清在线观看| 久久精品国产亚洲av涩爱| 国产一区亚洲一区在线观看| 成人亚洲精品av一区二区| 国产高潮美女av| 最近中文字幕高清免费大全6| 真实男女啪啪啪动态图| 日韩精品有码人妻一区| 国产精品国产三级国产专区5o| 成人亚洲欧美一区二区av| 亚洲最大成人av| 色尼玛亚洲综合影院| 婷婷色麻豆天堂久久| 丰满少妇做爰视频| 久久久久国产网址| 国产亚洲最大av| 久久精品国产亚洲av天美| 日韩欧美 国产精品| 日日干狠狠操夜夜爽| 成年女人在线观看亚洲视频 | 一二三四中文在线观看免费高清| 久久久久久久久中文| 99热网站在线观看| 麻豆av噜噜一区二区三区| 国产av码专区亚洲av| 亚洲av电影在线观看一区二区三区 | 亚洲自拍偷在线| 大香蕉97超碰在线| 国产白丝娇喘喷水9色精品| 精品久久国产蜜桃| 日日啪夜夜爽| 日本午夜av视频| 久久久久精品性色| 免费av不卡在线播放| 搡老乐熟女国产| 中文在线观看免费www的网站| 亚洲精品自拍成人| 18禁在线无遮挡免费观看视频| 内地一区二区视频在线| 蜜臀久久99精品久久宅男| av在线天堂中文字幕| 99热这里只有是精品在线观看| 免费观看av网站的网址| 一区二区三区免费毛片| 免费看光身美女| 亚洲欧洲日产国产| 丝瓜视频免费看黄片| 国产av在哪里看| 日本欧美国产在线视频| h日本视频在线播放| 床上黄色一级片| 亚洲久久久久久中文字幕| 男女啪啪激烈高潮av片| 五月天丁香电影| av免费在线看不卡| 日本三级黄在线观看| 国产三级在线视频| 国产麻豆成人av免费视频| 精品国产露脸久久av麻豆 | 国产又色又爽无遮挡免| 精品久久久久久久久av| 十八禁国产超污无遮挡网站| 免费av毛片视频| 韩国高清视频一区二区三区| 日韩一本色道免费dvd| 欧美日韩国产mv在线观看视频 | 国产激情偷乱视频一区二区| 国产一区亚洲一区在线观看| 国产乱人偷精品视频| 2021天堂中文幕一二区在线观| 好男人在线观看高清免费视频| 精品少妇黑人巨大在线播放| 国产精品av视频在线免费观看| 搡老妇女老女人老熟妇| 在线免费观看的www视频| 国产精品久久久久久精品电影小说 | 亚洲精品,欧美精品| 亚洲熟女精品中文字幕| 国模一区二区三区四区视频| 男女那种视频在线观看| 蜜臀久久99精品久久宅男| 午夜福利在线观看吧| 日韩电影二区| 汤姆久久久久久久影院中文字幕 | 国产探花在线观看一区二区| 亚洲精品成人久久久久久| 久久久久九九精品影院| kizo精华| 色综合亚洲欧美另类图片| 亚洲精品第二区| 国产白丝娇喘喷水9色精品| 国产伦精品一区二区三区视频9| 好男人视频免费观看在线| 老师上课跳d突然被开到最大视频| 国产精品综合久久久久久久免费| 免费大片18禁| 干丝袜人妻中文字幕| 插逼视频在线观看| 久久久久久久午夜电影| 熟女人妻精品中文字幕| 日韩国内少妇激情av| 国产欧美另类精品又又久久亚洲欧美| 午夜激情欧美在线| 精品少妇黑人巨大在线播放| 中文欧美无线码| 欧美日韩国产mv在线观看视频 | 国产精品精品国产色婷婷| 亚洲国产成人一精品久久久| 日本免费在线观看一区| 亚洲欧美成人综合另类久久久| 国产亚洲av嫩草精品影院| 国产又色又爽无遮挡免| 少妇被粗大猛烈的视频| 亚洲av电影在线观看一区二区三区 | 精品国产三级普通话版| 丰满乱子伦码专区| 精品久久久精品久久久| 极品少妇高潮喷水抽搐| 老司机影院毛片| 久久久久久久午夜电影| 国产淫语在线视频| 又粗又硬又长又爽又黄的视频| 国产 一区 欧美 日韩| 国产不卡一卡二| 久久草成人影院| 人人妻人人澡欧美一区二区| 少妇熟女欧美另类| 婷婷色麻豆天堂久久| 国产成人aa在线观看| 国产免费一级a男人的天堂| 男插女下体视频免费在线播放| 成年版毛片免费区| 美女内射精品一级片tv| 国产精品1区2区在线观看.| 久久99热这里只频精品6学生| 国产午夜精品论理片| 久久精品综合一区二区三区| 亚洲av中文字字幕乱码综合| 国产视频首页在线观看| 国产成人午夜福利电影在线观看| 我要看日韩黄色一级片| 日韩在线高清观看一区二区三区| 成人漫画全彩无遮挡| 国产又色又爽无遮挡免| 一级二级三级毛片免费看| 久久久精品免费免费高清| 天堂√8在线中文| 精品久久久噜噜| 99久久中文字幕三级久久日本| 九九爱精品视频在线观看| 哪个播放器可以免费观看大片| 国产精品国产三级国产专区5o| 午夜福利在线在线| 免费看av在线观看网站| 久久国产乱子免费精品| 久久久久久久国产电影| 九九久久精品国产亚洲av麻豆| 中文字幕亚洲精品专区| 26uuu在线亚洲综合色| 男人狂女人下面高潮的视频| 久久精品国产自在天天线| 国产精品伦人一区二区| 五月伊人婷婷丁香| 一级二级三级毛片免费看| 国内揄拍国产精品人妻在线| 亚洲国产精品成人综合色| 亚洲天堂国产精品一区在线| 2021天堂中文幕一二区在线观| 毛片女人毛片| 久久精品国产亚洲av涩爱| 亚洲自偷自拍三级| 久久人人爽人人片av| 午夜视频国产福利| 久久久久精品久久久久真实原创| 五月天丁香电影| 中文字幕免费在线视频6| 亚洲成人一二三区av| 成年版毛片免费区| 国产av不卡久久| 少妇人妻精品综合一区二区| 色综合色国产| 2018国产大陆天天弄谢| 久久久久久久国产电影| 黄色日韩在线| 舔av片在线| 色5月婷婷丁香| 我要看日韩黄色一级片| 成人午夜精彩视频在线观看| 亚洲av电影在线观看一区二区三区 | 久久99热6这里只有精品| 日产精品乱码卡一卡2卡三| 国产精品一二三区在线看| 亚洲成人精品中文字幕电影| 精品99又大又爽又粗少妇毛片| 日韩伦理黄色片| 亚洲图色成人| 在线免费观看的www视频| 成人美女网站在线观看视频| 久久久久久久午夜电影| 熟妇人妻久久中文字幕3abv| 国产精品久久久久久av不卡| 国产熟女欧美一区二区| 国产人妻一区二区三区在| 男女边摸边吃奶| 久久99热6这里只有精品| 亚洲熟女精品中文字幕| 色尼玛亚洲综合影院| 免费电影在线观看免费观看| 国产色婷婷99| 精品一区在线观看国产| 亚洲性久久影院| 搡老妇女老女人老熟妇| 三级男女做爰猛烈吃奶摸视频| 午夜免费激情av| 成人亚洲欧美一区二区av| av在线播放精品| 成人欧美大片| 免费av毛片视频| 女人被狂操c到高潮| 大话2 男鬼变身卡| 六月丁香七月| 国产黄片美女视频| 久久精品久久精品一区二区三区| 成人一区二区视频在线观看| 99久久精品热视频| 亚洲人成网站在线播| 国产一区二区三区av在线| 韩国高清视频一区二区三区| 日韩av在线免费看完整版不卡| 成年人午夜在线观看视频 | 亚洲国产精品专区欧美| 少妇人妻精品综合一区二区| 99视频精品全部免费 在线| 欧美激情在线99| 亚洲电影在线观看av| 亚洲精品成人久久久久久| 一级黄片播放器| 国产男女超爽视频在线观看| 少妇裸体淫交视频免费看高清| 一级毛片aaaaaa免费看小| 亚洲精品,欧美精品| 国产片特级美女逼逼视频| 亚洲经典国产精华液单| 亚洲自偷自拍三级| 国产91av在线免费观看| 国产精品无大码| 一级毛片我不卡| 国产伦一二天堂av在线观看| 亚洲欧洲日产国产| 国产亚洲av片在线观看秒播厂 | 视频中文字幕在线观看| 免费观看精品视频网站| 久久久久久久久大av| 色尼玛亚洲综合影院| 久久精品夜夜夜夜夜久久蜜豆| 干丝袜人妻中文字幕| 日韩人妻高清精品专区| 日本欧美国产在线视频| 成年版毛片免费区| 亚洲av一区综合| 成人午夜精彩视频在线观看| 欧美精品国产亚洲| av黄色大香蕉| freevideosex欧美| 午夜爱爱视频在线播放| 你懂的网址亚洲精品在线观看| 国产精品久久久久久av不卡| 可以在线观看毛片的网站| 国产精品久久久久久精品电影| 18禁动态无遮挡网站| 在线观看av片永久免费下载| 国产老妇伦熟女老妇高清| 在线a可以看的网站| 成人午夜高清在线视频| 天堂av国产一区二区熟女人妻| 久久久国产一区二区| 亚洲精品国产av蜜桃| 五月伊人婷婷丁香| 国产老妇伦熟女老妇高清| 寂寞人妻少妇视频99o| 少妇裸体淫交视频免费看高清| 亚洲精华国产精华液的使用体验| 精品一区二区免费观看| 亚洲不卡免费看| 成人国产麻豆网| 91精品国产九色| 精品人妻视频免费看| 三级毛片av免费| 边亲边吃奶的免费视频| 欧美xxxx黑人xx丫x性爽| 成人亚洲精品一区在线观看 | 日日啪夜夜爽| 免费电影在线观看免费观看| 国产成人精品一,二区| av免费在线看不卡| 日本三级黄在线观看| 国产成人91sexporn| videos熟女内射| 亚洲av免费在线观看| 女的被弄到高潮叫床怎么办| 国产真实伦视频高清在线观看| 天堂俺去俺来也www色官网 | 精品久久久久久电影网| 又爽又黄无遮挡网站| 国产精品国产三级专区第一集| 免费黄色在线免费观看| 免费观看av网站的网址| 美女cb高潮喷水在线观看| av福利片在线观看| 乱人视频在线观看| 日韩欧美一区视频在线观看 | 97人妻精品一区二区三区麻豆| 欧美xxxx性猛交bbbb| 三级男女做爰猛烈吃奶摸视频| 一个人免费在线观看电影| 啦啦啦韩国在线观看视频| 国产精品一及| 久久久久久久久久久丰满| 亚洲精品日韩av片在线观看| 久久人人爽人人片av| 纵有疾风起免费观看全集完整版 | 亚洲一区高清亚洲精品| 婷婷色麻豆天堂久久| 伊人久久精品亚洲午夜| 成人国产麻豆网| 精品99又大又爽又粗少妇毛片| 日韩伦理黄色片| 国产一级毛片在线| 五月伊人婷婷丁香| 久久精品国产鲁丝片午夜精品| 26uuu在线亚洲综合色| 九九爱精品视频在线观看| 菩萨蛮人人尽说江南好唐韦庄| videos熟女内射| 亚州av有码| 大又大粗又爽又黄少妇毛片口| 久久久国产一区二区| 午夜视频国产福利| 七月丁香在线播放| 蜜桃亚洲精品一区二区三区| 亚洲精品aⅴ在线观看| 亚洲综合精品二区| 99re6热这里在线精品视频| 欧美一区二区亚洲| 日本熟妇午夜| 久久精品久久精品一区二区三区| 久久鲁丝午夜福利片| 欧美zozozo另类| 国产黄片美女视频| 能在线免费看毛片的网站| 你懂的网址亚洲精品在线观看| 午夜福利视频1000在线观看| 国产精品1区2区在线观看.| 最后的刺客免费高清国语| 高清午夜精品一区二区三区| 国产亚洲av嫩草精品影院| 国产一级毛片七仙女欲春2| 亚洲国产色片| 日韩精品青青久久久久久| 99热全是精品| 少妇人妻一区二区三区视频| 久久久久久久大尺度免费视频| 日韩制服骚丝袜av| 日本一本二区三区精品| 少妇的逼好多水| 久久久欧美国产精品| 我要看日韩黄色一级片| 久久精品国产亚洲av涩爱| 在线观看免费高清a一片| 插逼视频在线观看| 久久久久网色| 大话2 男鬼变身卡| 久久精品夜色国产| 日韩欧美精品v在线| 久久草成人影院| 99久久精品热视频| 亚洲在线自拍视频| 丰满乱子伦码专区| 亚洲欧美日韩东京热| 欧美日韩国产mv在线观看视频 | 亚洲精品日本国产第一区| 国产高潮美女av| 免费黄色在线免费观看| av免费观看日本| 精品亚洲乱码少妇综合久久| 97超视频在线观看视频| 秋霞伦理黄片| 视频中文字幕在线观看| h日本视频在线播放| 99久国产av精品国产电影| 日韩欧美 国产精品| 日韩一区二区三区影片| 日本色播在线视频| 伊人久久国产一区二区| 国产av不卡久久| 97超碰精品成人国产| 亚洲欧美日韩卡通动漫| 亚洲国产高清在线一区二区三| 久99久视频精品免费| 97人妻精品一区二区三区麻豆| av线在线观看网站| 九色成人免费人妻av| 精品少妇黑人巨大在线播放| 欧美xxxx黑人xx丫x性爽| 男的添女的下面高潮视频| 色视频www国产| 婷婷六月久久综合丁香| 国产免费又黄又爽又色| 丰满乱子伦码专区| 亚洲欧美日韩东京热| 久久久久九九精品影院| 成人毛片60女人毛片免费| 国产乱来视频区|