炎症中的甜菜碱: 机制及其应用

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Betaine in Inflammation: Mechanistic Aspects and Applications

炎症中的甜菜碱: 机制及其应用

Abstract

摘要

Betaine is known as trimethylglycine and is widely distributed in animals, plants, and microorganisms. Betaine is known to function physiologically as an important osmoprotectant and methyl group donor. Accumulating evidence has shown that betaine has anti-inflammatory functions in numerous diseases. Mechanistically, betaine ameliorates sulfur amino acid metabolism against oxidative stress, inhibits nuclear factor-κB activity and NLRP3 inflammasome activation, regulates energy metabolism, and mitigates endoplasmic reticulum stress and apoptosis. Consequently, betaine has beneficial actions in several human diseases, such as obesity, diabetes, cancer, and Alzheimer’s disease.

甜菜碱被称为甜菜碱,广泛分布于动物、植物和微生物中。甜菜碱是一种重要的生理保护剂和甲基供体。越来越多的证据表明甜菜碱在许多疾病中具有抗炎作用。甜菜碱可以机械性地改善含硫氨基酸代谢对氧化应激的影响,抑制核因子 b 活性和 NLRP3炎症体的激活,调节能量代谢,减轻内质网应激和细胞凋亡。因此,甜菜碱对一些人类疾病有益,如肥胖症、糖尿病、癌症和阿尔茨海默氏症。Keywords: 关键词:betaine, oxidative stress, endoplasmic reticulum, inflammation, obesity 甜菜碱氧化应激内质网炎症肥胖

Introduction

引言

Betaine is a stable and nontoxic natural substance. Because it looks like a glycine with three extra methyl groups, betaine is also called trimethylglycine (1). In addition, betaine has a zwitterionic quaternary ammonium form [(CH3)3N+ CH2COO−] (Figure ​(Figure1).1). In the nineteenth century, betaine was first identified in the plant Beta vulgaris. It was then found at high concentrations in several other organisms, including wheat bran, wheat germ, spinach, beets, microorganisms, and aquatic invertebrates (2). Dietary betaine intake plays a decisive role in the betaine content of the body. Betaine is safe at a daily intake of 9–15 g for human and distributes primarily to the kidneys, liver, and brain (2). The accurate amount of betaine intake generally relies on its various sources and cooking methods (3). Besides dietary intake, betaine can be synthesized from choline in the body. Studies report that high concentrations of betaine in human and animal neonates indicate the effectiveness of this synthetic mechanism (45).

甜菜碱是一种稳定、无毒的天然物质。因为甜菜碱看起来像一个含有三个额外甲基的甘氨酸,所以甜菜碱也被称为甜菜碱。此外,甜菜碱具有两性离子季铵盐形式[(CH3)3N + CH2COO-](图1)。1).十九世纪,甜菜碱首次在植物甜菜中被鉴定出来。然后在其他一些生物体中发现了高浓度的该物质,包括麦麸、小麦胚芽、菠菜、甜菜、微生物和水生无脊椎动物(2)。食物中甜菜碱摄入量对人体甜菜碱含量起决定性作用。人每天摄入9-15克甜菜碱是安全的,主要分布于肾脏、肝脏和大脑(2)。甜菜碱摄入量的准确取决于甜菜碱的各种来源和烹饪方法。除了从日粮中摄入甜菜碱外,人体内的胆碱也可以合成甜菜碱。研究报告表明,高浓度的甜菜碱在人类和动物新生儿表明这一合成机制的有效性(4,5)。

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Figure 1 图1

(A) Molecular structure of betaine. (B) Metabolism of betaine and related sulfur amino acids (SAAs). Betaine is a substrate of choline and can be converted to DMG via demethylation to ultimately become glycine. Most of these reactions occur in the mitochondria. The demethylation reaction converts homocysteine to methionine and can be replaced by 5-methyl-THF, which can catalyze methylation to form THF. Then, methionine is successively converted to SAM and finally to homocysteine to form the methionine cycle. Homocysteine can also go through the transsulfuration pathway to form cystathionine, cysteine, taurine, or glutathione. The enzymes mentioned in this review are shown and marked in the cycle with individual numbers. 1. Betaine-homocysteine methyltransferase (BHMT); 2. Methionine synthase (MS); 3. Methionine adenosyltransferase (MAT); 4. SAM-dependent methyltransferases; 5. S-adenosylhomocysteine hydrolase; 6. Cystathionine β-synthase (CBS); 7. Cysteine dioxygenase (CDO); 8. γ-glutamylcysteine synthetase (GCS). THF, tetrahydrofolate; SAM, S-adenosyl-L-methionine; SAH S-adenosyl-L-homocysteine; DMG, N,N-dimethylglycine.

(a)甜菜碱的分子结构。(b)甜菜碱及相关硫化氨基酸(SAAs)的代谢。甜菜碱是胆碱的底物,可以通过去甲基化转化为甘氨酸。这些反应大多发生在线粒体中。去甲基化反应将同型半胱氨酸转化为蛋氨酸,并用5- 甲基四氢呋喃代替,催化甲基化生成四氢呋喃。甲硫氨酸先后转化为 SAM,最后转化为同型半胱氨酸,形成蛋氨酸循环。同型半胱氨酸也可以通过转硫途径形成半胱氨酸、半胱氨酸、牛磺酸或谷胱甘肽。本综述中提到的酶在循环中以单个数字显示和标记。1.甜菜碱-同型半胱氨酸甲基转移酶(BHMT) ;。蛋氨酸合成酶(MS) ;。甲硫氨酸腺苷转移酶; 4。依赖于 sam- 的甲基转移酶;。S-腺苷-L-高半胱氨酸; 6。胱硫醚合酶(CBS) ;。半胱氨酸双加氧酶(CDO) ;。- 谷氨酰半胱氨酸合成酶(GCS)。四氢呋喃,四氢叶酸; 山姆,S-腺苷甲硫氨酸; 蛛网膜下腔 S-腺苷-L-高半胱氨酸; DMG,n,n- 二甲基甘氨酸。

Regarding its biological significance, on the one hand, betaine is a vital methyl group donor in transmethylation, a process catalyzed by betaine-homocysteine methyltransferase (BHMT). This reaction catalyzes homocysteine to form methionine and occurs primarily in the liver and kidneys (6). On the other hand, betaine is an essential osmoprotectant, primarily in the kidneys, liver, and brain, and large amounts of betaine can accumulate in cells without disrupting cell function; importantly, this role of betaine protects cells, proteins, and enzymes under osmotic stress (7).

就其生物学意义而言,一方面,甜菜碱在转甲基化过程中是一个重要的甲基供体,该过程是由甜菜碱-同型半胱氨酸甲基转移酶(BHMT)催化的。这个反应催化同型半胱氨酸形成蛋氨酸,主要发生在肝脏和肾脏(6)。另一方面,甜菜碱是一种必需的渗透调节剂,主要存在于肾脏、肝脏和大脑,大量的甜菜碱可以在细胞中积累而不会破坏细胞功能; 重要的是,甜菜碱在渗透压胁迫下保护细胞、蛋白质和酶。

Recently, several studies have focused on various natural compounds proven to be effective against many diseases. For example, Geng and colleagues found that mulberrofuran G has anti-hepatitis B virus activity (8). Interestingly, in Southeast Asia, water extracts of Lycium chinensis, which contains a high concentration of betaine, were used as a traditional oriental medicine to treat liver disorders (9). These findings indicate that the function of betaine, a natural compound, has become a hot topic because of its anti-inflammatory effects on diseases, such as nonalcoholic and alcoholic fatty liver disease (NAFLD and AFLD) and diabetes (1012). This paper summarizes the role of betaine in physiological functions, anti-inflammatory mechanisms, and human diseases.

最近,一些研究集中在各种天然化合物被证明对许多疾病有效。例如,耿和他的同事们发现,黑龙江呋喃 g 具有抗乙肝病毒活性(8)。有趣的是,在东南亚,含有高浓度甜菜碱的枸杞水提取物被用作治疗肝脏疾病的传统汉医学。这些发现表明甜菜碱,一种天然化合物,由于其对疾病的抗炎作用,如非酒精性和脂肪肝性疾病(NAFLD 和 AFLD)和糖尿病(10-12) ,已经成为一个热门话题。本文综述了甜菜碱在生理功能、抗炎机制和人类疾病中的作用。Go to: 去:

Physiological Functions of Betaine

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甜菜碱的生理功能

As many studies show, cells from bacteria to vertebrates absorb betaine as an osmoprotectant; animals can rapidly absorb betaine through the duodenum of the small intestine (1314). Specifically, betaine can be freely filtered in the kidney and reabsorbed into the circulation, so it is primarily excreted in sweat instead of urine (1516). Betaine accumulation depends on transporters, and it primarily distributes to the kidneys, liver, and brain (2). Although betaine is utilized in most tissues (such as the kidneys and brain) as an osmoprotectant, its primary role is to act as a methyl group donor in liver metabolism (1718).

许多研究表明,从细菌到脊椎动物的细胞以渗透调节剂的形式吸收甜菜碱; 动物可以通过小肠的十二指肠迅速吸收甜菜碱(13,14)。具体来说,甜菜碱可以在肾脏中被自由过滤并被循环系统重新吸收,所以它主要以汗液而不是尿液的形式排出(15,16)。甜菜碱的积累依赖于转运蛋白,主要分布于肾脏、肝脏和脑(2)。虽然甜菜碱在大多数组织(如肾脏和脑)中被用作渗透调节剂,但其主要作用是作为肝脏代谢的甲基供体(17,18)。

Betaine as an Osmoprotectant

甜菜碱作渗透调节保护剂

In contrast to inorganic salts, osmoprotectants are highly soluble small organic compounds that accumulate in large amounts in cells without disrupting cell function; these compounds protect against osmotic stress (19). Hyperosmosis can cause water efflux and a concomitant reduction in cell volume; these effects are detrimental to cell survival (20). Thus, to balance hyperosmosis and protect cells from shrinkage and death, the accumulation of different types of osmoprotectants, such as betaine, sorbitol, and taurine, is essential (2125). In contrast to other osmolytes and inorganic salts, such as urea and Na+, betaine reduces the ability of water molecules to solvate proteins, thus stabilizing the native protein structures (26). In addition, betaine can also increase the cytoplasmic volume and free water content of cells to prevent shrinkage in hyperosmotic conditions and to inhibit various hyperosmotic-induced apoptosis-related proteins (2728). Due to these advantages, additional betaine can be used to counter the pressure when tissues are hypertonic. For example, in the kidneys, hypertonicity increases the levels of the betaine-γ-aminobutyric acid (GABA) transport system (GAT4/BGT1) in the basolateral plasma membrane to obtain more betaine; however, under normal physiological conditions, BGT1 levels are low, and this transporter is present primarily in the cytoplasm in Madin–Darby canine kidney (MDCK) cells (21).

与无机盐相比,渗透调节物质是高度可溶的小型有机化合物,它们在细胞中大量积累而不破坏细胞功能; 这些化合物可以抵御渗透压胁迫。高渗透可导致水分外流和随之而来的细胞体积减少,这些影响对细胞存活是有害的。因此,为了平衡高渗透和保护细胞免于萎缩和死亡,不同类型的渗透保护剂,如甜菜碱、山梨醇和牛磺酸的积累是必不可少的(21-25)。与其他渗透剂和无机盐(如尿素和钠离子)相比,甜菜碱降低了水分子溶解蛋白质的能力,从而稳定了天然蛋白质结构(26)。此外,甜菜碱还可以增加细胞质体积和游离水含量,以防止在高渗条件下萎缩和抑制各种高渗诱导的凋亡相关蛋白(27,28)。由于这些优点,当组织处于高渗状态时,可以使用额外的甜菜碱来对抗压力。例如,在肾脏中,高渗性增加了基底外侧质膜中的蛋白-氨基丁酸(GAT4/BGT1)转运系统的水平以获得更多的甜菜碱,然而,在正常生理条件下,BGT1水平较低,这种转运蛋白主要存在于 Madin-达比犬肾细胞(MDCK)中。

Betaine as a Methyl Group Donor

甜菜碱作为甲基供体

Betaine is not only a metabolite of choline but also a methyl group donor that participates in methylation. Methylation, such as that of DNA and protein, is an essential biochemical process in animals. A previous study has shown that the availability of methyl group donors influences methylation levels (29). It has been acknowledged that betaine, methionine, and choline are the most important methyl group donors present in diets. Nevertheless, the major role of methionine is a substrate for protein synthesis, and choline contributes primarily to forming the cell membrane and neurotransmitters. The transmethylation reaction of betaine, which is part of a one-carbon metabolism via the methionine cycle, occurs principally in the mitochondria of liver and kidney cells. In this reaction, BHMT catalyzes the addition of a methyl group from betaine to homocysteine to form methionine, which is subsequently converted to dimethylglycine (DMG) (30). DMG has two available methyl groups and is possibly degraded to sarcosine and ultimately to glycine. Similarly, methionine synthase (MS), a vitamin B12-dependent enzyme, can also catalyze the formation of methionine from homocysteine with a donor methyl group from N5-methyltetrahydrofolate. These reactions are important in animals because they conserve methionine, detoxify homocysteine, which is a cause of cardiovascular disease (31), and produce S-adenosylmethionine (SAM) (32). SAM is generated from methionine via methionine adenosyltransferase (MAT), and SAM is a principal methylating agent. After demethylation, SAM is transformed into S-adenosylhomocysteine (SAH). The ratio of SAM:SAH affects various SAM-dependent methyltransferases, including protein-L-isoaspartate methyltransferase (PIMT), phosphatidylethanolamine methyltransferase (PEMT), protein arginine methyltransferase (PRMT), and isoprenylcysteine carboxyl methyltransferase (ICMT). These enzymes are associated with the protein repair progress, lipid metabolism, protein–protein interactions, and GTPase activity (3338). One molecule of SAH is subsequently hydrolyzed by SAH hydrolase to form one homocysteine molecule and one adenosine molecule. Notably, this reaction is reversible, and the direction of the reaction depends on whether these products are removed. All of these reactions constitute the methionine cycle. Furthermore, with the help of cystathionine β-synthase, a vitamin B-6-dependent enzyme, homocysteine can be transformed into cystathionine via the transsulfuration pathway. In this pathway, homocysteine catabolism leads to an increase in the production of glutathione (GSH), taurine, and other metabolites (3941). Dietary betaine supplementation has been demonstrated to have an impact on various sulfur amino acids (SAAs) (2). For example, such supplementation effectively increases the available methionine and SAM (4243). Therefore, betaine acts as a methyl donor and plays an influential role in SAA metabolism; the details of this metabolic pathway are shown in Figure ​Figure11B.

甜菜碱不仅是胆碱的代谢产物,而且是参与甲基化的甲基供体。甲基化,如 DNA 和蛋白质的甲基化,是动物体内一个重要的生化过程。先前的研究表明甲基基团供体的可用性影响甲基化水平(29)。已经承认甜菜碱、蛋氨酸和胆碱是在饮食中最重要的甲基群供体。尽管如此,蛋氨酸的主要作用是蛋白质合成的底物,而胆碱主要贡献于形成细胞膜和神经递质。甜菜碱的转甲基化反应是通过蛋氨酸循环进行的一碳代谢的一部分,主要发生在肝和肾细胞的线粒体中。在这个反应中,BHMT 催化一个甲基从甜菜碱加成同型半胱氨酸形成蛋氨酸,然后转化为二甲基甘氨酸(DMG)(30)。DMG 有两个可用的甲基基团,可能降解为肌氨酸并最终降解为甘氨酸。同样,甲硫氨酸合成酶(MS)是一种维生素 b12依赖性酶,也能催化同型半胱氨酸与 n5- 甲基四氢叶酸甲基形成甲硫氨酸。这些反应在动物身上很重要,因为它们储存蛋氨酸,解除引起心血管疾病的同型半胱氨酸,并产生 S-腺苷甲硫氨酸。SAM 是蛋氨酸通过甲硫氨酸腺苷转移酶产生的,SAM 是主要的甲基化剂。去甲基化后,SAM 转化为 S-腺苷-L-高半胱氨酸。SAM 与 SAH 的比例影响各种 SAM 依赖的甲基转移酶,包括蛋白质 l- 异天冬氨酸甲基转移酶(PIMT)、磷脂酰乙醇胺甲基转移酶(PEMT)、蛋白质精氨酸甲基转移酶(PRMT)和异戊半胱氨酸羧基甲基转移酶(ICMT)。这些酶与蛋白质修复进程、脂质代谢、蛋白质-蛋白质相互作用和 GTPase 活性(33-38)有关。一个 SAH 分子随后被 SAH 水解酶水解,形成一个同型半胱氨酸分子和一个腺苷分子。值得注意的是,这个反应是可逆的,反应的方向取决于这些产物是否被除去。所有这些反应构成蛋氨酸循环。此外,在维生素 b6依赖性酶胱硫醚合成酶的帮助下,同型半胱氨酸可通过转硫途径转化为胱硫醚。在这个途径中,同型半胱氨酸分解代谢导致谷胱甘肽(GSH) ,牛磺酸和其他代谢物(39-41)的生产增加。日粮中添加甜菜碱对各种含硫氨基酸(SAAs)有影响(2)。例如,这种补充有效地增加了可利用的蛋氨酸和 SAM (42,43)。因此,甜菜碱作为甲基供体,在 SAA 的新陈代谢中起着重要作用; 这种代谢途径的细节见图11 b。Go to: 去:

Anti-Inflammatory Effects of Betaine on Diseases

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甜菜碱对疾病的抗炎作用

Inflammation, an immune reaction, is an essential and primary process of host defense and wound healing. However, excessive or prolonged inflammation may become the pathogenesis of various diseases. Due to this, using natural compounds to treat diseases could be a good strategy by controlling the intensity of the inflammatory reaction. For instance, many studies show that GABA is anti-inflammatory (44). Consequently, using betaine in response to inflammation has sparked heated debate in recent years. Next, this review will discuss the primary mechanisms through which betaine exerts its anti-inflammatory effects on diseases.

炎症是一种免疫反应,是宿主防御和伤口愈合的基本过程。炎症反应过度或持续时间过长可能成为各种疾病的发病机制。因此,利用天然化合物治疗疾病可能是一个很好的策略,通过控制炎症反应的强度。例如,许多研究表明 GABA 具有抗炎作用。因此,使用甜菜碱应对炎症已经引起了激烈的辩论在最近几年。接下来,我们将讨论甜菜碱对疾病发挥抗炎作用的主要机制。

Betaine Ameliorates SAA Metabolism Against Oxidative Stress

甜菜碱改善 SAA 代谢对氧化应激的影响

Reactive oxygen species (ROS) are by-products of biological energy-generating reactions; in particular, they are produced in the mitochondria where oxidative metabolism primarily occurs. Under normal conditions, the body has two detoxification systems that can clear ROS and free radicals: antioxidant enzymes and antioxidant agents (4546). Catalase, superoxide dismutase (SOD), melatonin, and GSH are examples of these detoxification agents (4749). However, excess ROS levels are a threat to cells because they alter the stability of nucleic acids, proteins, and the lipid membrane; furthermore, high ROS levels likely cause pathological processes, including inflammation (50).

活性氧类(ROS)是生物能量产生反应的副产品,特别是,它们产生于线粒体,主要发生唿吸作用。在正常情况下,人体有两个清除活性氧和自由基的解毒系统: 抗氧化酶和抗氧化剂(45,46)。过氧化氢酶、超氧化物歧化酶(SOD)、褪黑激素和谷胱甘肽就是这些解毒剂的例子(47-49)。然而,过高的活性氧水平对细胞是一种威胁,因为它们改变了核酸、蛋白质和脂膜的稳定性; 此外,过高的活性氧水平可能引起包括炎症在内的病理过程。

Sulfur amino acids such as homocysteine, methionine, SAM, SAH, and cysteine are involved in various essential metabolic pathways, including GSH synthesis and protein synthesis, and transmethylation reactions. Although homocysteine contributes to GSH synthesis (51), various studies have demonstrated that hyperhomocysteinemia ultimately induces oxidative stress and apoptosis (5253). Betaine treatment can directly influence homocysteine concentrations via stimulating homocysteine to form methionine to regulate SAA concentrations. For example, ethanol-induced ROS and free radicals can suppress methionine synthase (MS) activity to inhibit remethylation and induce hyperhomocysteinemia (54). To compensate for this decrease in MS activity, betaine was used as an alternate methyl donor that improved BHMT activity to generate methionine and SAM and remove homocysteine in the livers of ethanol-fed Wistar rats (5455). However, it is worth noting that C57B6 mice showed a decrease or no change in BHMT expression, rather than a compensational increase (56). As betaine converts homocysteine to methionine, methionine concentrations are closely related with betaine. Methionine plays an important role in antioxidation. For example, methionine can reduce oxidative stress via chelation, and it can be used by hepatocytes for GSH synthesis (5758). In addition, this reaction is essential for generating SAM and removing homocysteine. Studies have demonstrated that SAM is a direct antioxidant in the body and that it can modulate GSH metabolism (5960). Moreover, based on the reversibility of the reaction that converts SAH to homocysteine and adenosine, homocysteine concentrations would further decrease (61). SAH is a powerful inhibitor of SAM-dependent methyltransferases; which methylate various compounds, such as nucleic acids and proteins (62). Kwon and colleagues found that betaine could significantly increase the SAM:SAH ratio and MAT activity (63). Kharbanda and colleagues found that betaine could prevent nitric oxide synthase 2(NOS2) expression; this process is initiated by inflammation, and the SAM:SAH ratio is increased to maintain NOS2 promoter methylation (64). In addition, homocysteine can also be converted to cysteine via the irreversible transsulfuration pathway, and cysteine then forms either taurine via cysteine dioxygenase (CDO) or GSH via γ-glutamylcysteine synthetase (65). Researchers found that betaine treatment inhibited CDO activity and decreased taurine levels, while increased the production of GSH to neutralize oxidative stress in AFLD and NAFLD mice (116366).

硫氨基酸如同型半胱氨酸、甲硫氨酸、 SAM、 SAH 和半胱氨酸参与了各种基本代谢途径,包括 GSH 合成和蛋白质合成,以及转甲基化反应。虽然同型半胱氨酸有助于谷胱甘肽的合成(51) ,各种研究表明,高同型半胱氨酸血症最终诱导氧化应激和细胞凋亡(52,53)。甜菜碱处理通过刺激同型半胱氨酸生成蛋氨酸来调节 SAA 的浓度,从而直接影响同型半胱氨酸的浓度。例如,乙醇诱导的活性氧和自由基可以抑制蛋氨酸合成酶(MS)活性以抑制再甲基化和诱导高同型半胱氨酸血症(54)。为了补偿 MS 活性的下降,用甜菜碱作为替代甲基供体,改善 BHMT 活性,生成蛋氨酸和 SAM,并去除乙醇喂养的 Wistar 大鼠(54,55)肝脏中的同型半胱氨酸。然而,值得注意的是 C57B6小鼠 BHMT 表达减少或没有变化,而不是代偿性增加(56)。当甜菜碱将同型半胱氨酸转化为蛋氨酸时,蛋氨酸的浓度与甜菜碱密切相关。蛋氨酸在抗氧化中起着重要作用。例如,蛋氨酸可以通过螯合作用减少氧化应激,肝细胞可以用它来合成谷胱甘肽(57,58)。此外,这一反应对 SAM 的产生和同型半胱氨酸的去除至关重要。研究表明,SAM 是一种直接的抗氧化剂,在体内,它可以调节谷胱甘肽代谢(59,60)。此外,基于 SAH 转化为同型半胱氨酸和腺苷反应的可逆性,同型半胱氨酸浓度将进一步降低(61)。SAH 是 sam- 依赖的甲基转移酶的强有力的抑制剂,它使各种化合物,如核酸和蛋白质(62)甲基化。Kwon 和他的同事发现甜菜碱可以显著提高 SAM: SAH 比率和 MAT 活性(63)。和他的同事发现甜菜碱可以阻止一氧化氮合酶2(NOS2)的表达,这个过程是由炎症引起的,SAM: SAH 比率增加以维持 NOS2启动子甲基化(64)。此外,同型半胱氨酸也可以通过不可逆的转硫途径转化为半胱氨酸,半胱氨酸通过半胱氨酸双加氧酶(CDO)或谷氨酰半胱氨酸合成酶(65)形成牛磺酸。研究人员发现,甜菜碱处理抑制 CDO 活性,降低牛磺酸水平,同时增加谷胱甘肽的产生,以中和 AFLD 和 NAFLD 小鼠(11,63,66)的氧化应激。

Few studies indicated antioxidant enzymes, such as SOD 2 and glutathione S-transferases (GST), were changed after betaine treatment, but most results have shown no significant changes. Thus, more researches are needed in the future to confirm whether these antioxidant enzymes really participated in the process (556768). Considering the above studies, the primary antioxidant mechanism of betaine may occur through ameliorating SAA metabolism. These changes after betaine treatment and the oxidation-related functions of primary SAAs are shown in Table ​Table11.

几乎没有研究表明甜菜碱处理后抗氧化酶,如 SOD 2和谷胱甘肽 s- 转移酶(GST)发生了变化,但大多数研究结果没有显示出明显的变化。因此,今后需要更多的研究来确认这些抗氧化酶是否真的参与了这一过程(55,67,68)。综上所述,甜菜碱的主要抗氧化机制可能是通过改善 SAA 代谢来实现的。甜菜碱处理后的这些变化和主要 SAAs 的氧化相关功能见表11。

Table 1

表一

Changes in the oxidation-related functions of primary sulfur amino acids after betaine treatment.

甜菜碱处理后初生含硫氨基酸氧化相关功能的变化。

Compound 化合物Change 改变Functions 功能Reference参考资料
Methionine 蛋氨酸Upregulated 上升GSH synthesis; reduces oxidative stress 谷胱甘肽合成; 减少氧化应激(575869)
S-adenosylmethionine S-腺苷甲硫氨酸Upregulated 上升Increases cellular GSH content; antioxidant 增加细胞内谷胱甘肽含量; 抗氧化剂(5960)
S-adenosylhomocysteine S-腺苷-L-高半胱氨酸Downregulated降低监管Inhibits methyltransferases 抑制甲基转移酶(62)
Induces oxidative stress 诱导氧化应激
Homocysteine 同型半胱氨酸Downregulated降低监管Induces oxidative stress; GSH synthesis 诱导氧化应激; 谷胱甘肽合成(515370)
Cysteine 半胱氨酸Upregulated 上升GSH synthesis; reduces oxidative stress 谷胱甘肽合成; 减少氧化应激(65)
GSH 谷胱甘肽Upregulated 上升Antioxidant 抗氧化剂(71)

Betaine Inhibits the NF-κB Signaling Pathway

甜菜碱抑制 nf-b 信号通路的研究

The pathway of the transcription factor nuclear factor-κB (NF-κB) controls many genes involved in inflammation; these genes include the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1β) and interleukin 23 (IL-23). Therefore, it is not surprising that many inflammatory diseases involve chronically activation of NF-κB (7274). Consequently, the NF-κB pathway has become an essential candidate for inflammation treatment. Researchers found that betaine can suppress NF-κB activity and various downstream genes (7577). For example, in an early study of aged kidneys, betaine treatment suppressed NF-κB activity and the expression of a variety of related genes, including TNF-α, vascular cell adhesion molecule-1 (VCAM-1), intracellular cell adhesion molecule-1 (ICAM-1), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) (75). Notably, in this and another study about atherogenesis, the authors found that betaine inhibited NF-κB by suppressing two important activators, mitogen-activated protein kinases (MAPKs) and nuclear factor-inducing kinase/IκB kinase (NIK/IKK) (7576). NIK/IKK can relieve IκB inhibition and initiate the transcriptional activation of NF-κB (78). MAPKs consist of c-Jun NH2-terminal kinase (JNK), protein 38 (p38), and extracellular signal-regulated kinase (ERK1/2) and are involved in inflammation and the response to pro-inflammatory cytokine expression (79). Mechanistically, betaine exerts its effects by maintaining thiol levels, particularly GSH, to inhibit ROS production and NF-κB activity (80). Furthermore, betaine also inhibits some upstream signaling molecules that induce the activation of NF-κB. Classically, Toll-like receptors (TLRs) participate in an important upstream signaling event, which eventually culminates in activating NF-κB. In an in vitro study, betaine treatment prevented lipopolysaccharide (LPS, specific activator of TLR-4)-induced NF-κB activation in RAW 264.7 murine macrophage cells (81). Another study showed that betaine treatment improved hypothalamic neural injury via inhibiting the TLR-4/NF-κB signaling pathway to restore fructose-induced astrogliosis and inflammation. This study suggests that betaine can inhibit histone deacetylases 3 expression, which can activate NF-κB via binding to IκBα (82). Another study showed that betaine treatment can reduce the mRNA and protein expression levels of high-mobility group box 1, a positive regulator of TLR-4 activation to restrict inflammation (83). In addition, betaine can also reduce endogenous damage-associated molecular pattern (DAMP) generation to inhibit the NF-κB pathway. In conclusion, betaine has anti-inflammatory effects through its inhibition of NF-κB signaling pathway.

转录因子细胞核因子 b (nf- b)通路控制着许多与炎症有关的基因,这些基因包括促炎细胞因子肿瘤坏死因子 α (tnfα)、白细胞介素-1β 细胞因子1(il-1)和白细胞介素23(IL-23)。因此,许多炎症性疾病与 nf- b (72-74)的慢性激活有关就不足为奇了。因此,nf-b 途径已成为炎症治疗的重要候选途径。研究人员发现甜菜碱可以抑制 nf- b 活性和各种下游基因(75-77)。例如,在老化肾脏的早期研究中,甜菜碱处理抑制了 nf- b 的活性和多种相关基因的表达,包括 tnf-、血管细胞粘附分子 -1(VCAM-1)、细胞内粘附分子 -1(ICAM-1)、诱导型一氧化氮合酶(iNOS)和环氧合酶 -2(COX-2)(75)。值得注意的是,在这项和另一项关于动脉粥样硬化形成的研究中,作者发现甜菜碱通过抑制两种重要的激活因子,丝裂原活化蛋白激酶(MAPKs)和核因子诱导激酶/i b 激酶(NIK/IKK)(75,76)来抑制 nf- b。NIK/IKK 可以减轻 i b 抑制,启动 nf- b 的转录激活。MAPKs 包括 c-Jun 氨基末端激酶(c-Jun NH2-terminal kinase,JNK)、蛋白38(protein 38,p38)和细胞外信号调节激酶(extracellular signal-regulated kinase,ERK1/2) ,参与炎症反应和对促炎细胞因子表达的反应(79)。机制上,甜菜碱通过维持巯基水平,特别是谷胱甘肽,来抑制活性氧的产生和 nf- b 活性(80)来发挥作用。此外,甜菜碱还抑制一些诱导 nf- b 激活的上游信号分子。经典的 toll 样受体(TLRs)参与重要的上游信号事件,最终激活 nf- b。在一项体外研究中,甜菜碱处理可以阻止 LPS (TLR-4特异性激活剂)诱导 RAW 264.7小鼠巨噬细胞(81)中 nf- b 的活化。另一项研究表明,甜菜碱治疗改善下丘脑神经损伤通过抑制 TLR-4/nf- b 信号通路恢复果糖诱导的星形胶质细胞病和炎症。提示甜菜碱能抑制组蛋白去乙酰化酶3的表达,通过与 i b (82)结合激活 nf- b。另一项研究表明,甜菜碱处理可以降低高迁移率族蛋白1的 mRNA 和蛋白表达水平,该蛋白是 TLR-4激活抑制炎症的正向调节因子(83)。此外,甜菜碱还可以减少内源性损伤相关分子模式(DAMP)的产生,从而抑制 nf-b 通路。结论: 甜菜碱通过抑制 nf-b 信号通路具有抗炎作用。

Betaine Inhibits NLRP3 Inflammasome Activation

甜菜碱抑制 NLRP3炎症体激活

The leucine-rich family, pyrin-containing 3 (NLRP3) inflammasome is a large cytosolic protein complex that contains the nucleotide-binding domain, leucine-rich repeat-containing (NLR) family member NLRP3, the important adapter molecule ASC, and mature caspase-1. When TLRs recognize DAMPs or pathogen-associated molecular patterns, NF-κB can be activated to promotes mRNA expression of interleukin precursors, including pro-IL-18 and pro-IL-1β, as well as NLRP3 (84). The completely assembled NLRP3 inflammasome activates caspase-1 to mediate the production of mature IL-1β and IL-18, which are involved in initiating inflammation (85). It is important to ameliorate inflammatory reactions via inhibiting NLRP3 inflammasome activity.

含有高亮氨酸的3(NLRP3)炎性蛋白质家族是一个包含核苷酸结合域、高亮氨酸重复序列(NLR)家族成员 NLRP3、重要的连接分子 ASC 和成熟的 caspase-1的大型胞浆蛋白复合体。当 TLRs 识别 DAMPs 或病原体相关分子模式时,nf- b 可被激活,促进白细胞介素前体 mRNA 的表达,包括前 il-18和前 il-1,以及 NLRP3(84)。完全组装的 NLRP3炎症体激活 caspase-1介导成熟的 il-1和 IL-18的产生,这些参与引发炎症(85)。通过抑制 NLRP3炎症活性改善炎症反应具有重要意义。

Earlier studies have shown that betaine can directly increase heme oxygenase-1 expression levels in hepatocytes (86); this effect may suppress the NLRP3 inflammasome to protect against LPS-induced and d-galactosamine-induced inflammation in the liver (8788). Recent studies have demonstrated that betaine treatment can significantly inhibit NLRP3 inflammasome-related proteins, such as NLRP3 and mature caspase-1, and the levels of pro-inflammatory cytokines, including IL-1β, in a dose-independent manner in fructose-induced NAFLD models (828990). The same phenomenon was found in betaine-treated db/db mice; this finding shows that the mechanism is associated with a forkhead box O1 (FOXO-1) inhibition of thioredoxin-interacting protein (TXNIP), which can promote the production of ROS to trigger NLRP3 inflammasome assembly (12). The FOXO family contains six members, including FOXO-1 and FOXO-6, that are found in mammals. The main role of FOXO factors is the regulation of cell growth, cell death, proliferation, differentiation, and oxidative stress response (9192). Activated FOXO-1 promotes TXNIP activity, which is the endogenous inhibitor of ROS-scavenging protein thioredoxin, resulting in producing more ROS (93). In addition, activated PKB/Akt can phosphorylate the active form of FOXO-1 to trigger its exit from the nucleus into the cytoplasm; this change makes FOXO-1 inactivation (94). In this study, betaine treatment increased the levels of PKB/Akt-mediated FOXO-1 phosphorylation. However, Kathirvel and colleagues noted that betaine did not directly activate PKB/Akt, and its mechanism may be the result of enhanced insulin receptor substrate 1 (IRS-1) phosphorylation (10). Thus, we suggest that betaine could enhance IRS-1 activity to activate PKB/Akt; then, the activated PKB/Akt would inhibit FOXO-1 activation, which restricts TXNIP to suppress NLRP3 inflammasome components to excise its anti-inflammation effects. Moreover, a study found that betaine mediated inhibition of NLRP3 inflammasome activation played a more important role than that of NF-κB in response to renal inflammation (90). Overall, the anti-inflammatory effects of betaine are closely associated with its inhibition of NLRP3 inflammasome activation.

早期研究表明,甜菜碱可直接增加血红素氧合酶 -1在肝细胞中的表达水平(86) ,这种作用可能抑制 NLRP3炎症体,以保护肝脏免受脂多糖诱导的和 d- 半乳糖胺诱导的炎症反应(87,88)。近年来的研究表明,甜菜碱处理对果糖诱导的 NAFLD 模型(82,89,90)中 NLRP3、成熟 caspase-1等炎症相关蛋白以及 il-1等促炎细胞因子的表达具有剂量依赖性的抑制作用。在甜菜碱处理的 db/db 小鼠中也发现了同样的现象,这一发现表明这一机制与叉头盒 O1(FOXO-1)抑制硫氧还蛋白相互作用蛋白(TXNIP)有关,该蛋白可促进 ROS 的产生,从而触发 NLRP3炎性组件(12)。FOXO 家族包括6个成员,包括 FOXO-1和 FOXO-6,这些成员都是在哺乳动物中发现的。FOXO 因子的主要作用是调节细胞生长、细胞死亡、增殖、分化和氧化应激反应(91,92)。活化的 FOXO-1促进内源性蛋白硫氧还蛋白抑制剂 TXNIP 活性,产生更多的 ROS (93)。此外,活化的 PKB/Akt 可以磷酸化 FOXO-1的活性形式,从而触发其从细胞核进入细胞质,这种变化使 FOXO-1失活(94)。在本研究中,甜菜碱处理增加了 pkb/akt 介导的 FOXO-1磷酸化水平。然而,Kathirvel 和他的同事们注意到甜菜碱不能直接激活 PKB/Akt,其机制可能是增强的胰岛素受体底物1(IRS-1)磷酸化(10)的结果。因此,我们认为甜菜碱能增强 IRS-1活性,激活 PKB/Akt,抑制 FOXO-1活性,从而限制 TXNIP 抑制 NLRP3炎症组分,消除其抗炎作用。此外,一项研究发现,甜菜碱介导的抑制 NLRP3炎症体激活在肾脏炎症反应中起着比 nf- b 更重要的作用(90)。总之,甜菜碱的抗炎作用与其抑制 NLRP3炎症体激活密切相关。

Betaine Regulates Energy Metabolism to Relieve Chronic Inflammation

甜菜碱调节能量代谢缓解慢性炎症

Energy metabolism disorders can lead to various chronic diseases, including obesity and diabetes, which generally have a systemic low-grade inflammation (95). Thus, restoring normal metabolism is an essential step that contributes to mitigating inflammation. As various reports have reported, betaine has effects on both lipid and glucose metabolism (1096). Regarding lipid metabolism, excessive fat accumulation resulting from the imbalance of lipid transportation, synthesis, and oxidation is considered to be the culprit of many diseases. Many studies have demonstrated that various factors, such as high-fat diets, antibiotics exposure and ethanol consumption, could lead to such situations (1197).

能量代谢紊乱可导致各种慢性疾病,包括肥胖和糖尿病,这些疾病通常具有全身性低度炎症(95)。因此,恢复正常的新陈代谢是有助于减轻炎症的必要步骤。正如各种报道所报道的,甜菜碱对糖代谢和脂代谢都有影响(10,96)。对于脂质代谢,脂肪运输、合成和氧化失衡导致的过度脂肪堆积被认为是许多疾病的罪魁祸首。许多研究表明,各种因素,如高脂肪饮食,抗生素接触和乙醇消费,可能导致这种情况(11,97)。

Betaine treatment can restore the imbalance between synthesis and oxidation to help attenuate fat accumulation (9799). Song and colleagues found that an increased hepatic AMP-activated protein kinase (AMPK) activity may be involved mechanistically (98). AMPK serves as both a principal cellular energy sensor and a vital metabolic homeostasis regulator; in fact, AMPK controls many genes, such as sterol regulatory element-binding protein-1c (SREBP-1c), acetyl CoA carboxylase (ACC), and fatty acid synthase (FAS). Activated AMPK can inhibit fatty acid synthesis and promote fatty acid oxidation viaregulating the expression of these genes (100). Betaine can increase AMPK phosphorylation and then inhibit ACC activity as well as SREBP-1c and FAS expression (98). This result supports the finding of another study in which AMPK could directly phosphorylate SREBP-1c and SREBP-2 at Ser372 to inhibit their activities to reduce lipogenesis and lipid accumulation in diet-induced insulin-resistant mice (101). Furthermore, activated AMPK promotes glucose uptake via improving glucose transporter type 4 (GLUT-4) translocation; these findings suggest a beneficial effect on insulin resistance (102). Regarding the mechanism of AMPK activation, changing the AMP:ATP ratio in cells under normal conditions activates AMPK (103). However, hepatic AMPK activation can occur independently of the AMP:ATP ratio viaadiponectin (104105). Interestingly, in another study from Song, betaine could restore abnormal adipokine levels in NAFLD, and it upregulated adiponectin and downregulated leptin and resistin in adipose cells to attenuate the dysregulated lipid metabolism. Similar effects of betaine are supported by another in vitrostudy in human adipocytes (106). These results imply that the upregulation of adiponectin may contribute to AMPK phosphorylation (107). In addition, because these adipokines play roles in inflammation, this normalizing process is anti-inflammatory (106). In addition to activating AMPK, betaine treatment could potentially influence other lipid metabolism-related factors. Earlier studies showed that betaine can reduce triglyceride accumulation in apolipoprotein B (apoB)-deficient mice via decreasing peroxisomal proliferator-activated receptor alpha (PPARα) methylation (108). In another study, betaine restricted PPARγ transcriptional activity via inhibiting FOXO-1 binding to the PPARγ promoter to reduce fat accumulation (109). In a recent study, not only PPARα but also hepatic liver X receptor α (LXRα) were upregulated when betaine restored fatty acid oxidation inhibition (89). Although the mechanism of how betaine activates LXRα remains unclear, it may be associated with a SAM-related enzyme PRMT-3, which can directly increase LXRα activity (38). In addition, in a study of cisplatin-induced nephrotoxicity, betaine inhibited lipid peroxidation via suppressing renal thiobarbituric acid-reactive substance activation, which is mostly initiated by oxidative stress (110). In addition to altering fat synthesis and oxidation, betaine treatment can ameliorate lipid transport. A study found that betaine maintains liver SAM:SAH ratios to enhance phosphatidylcholine synthesis and normalize very-low-density lipoprotein (VLDL) production viapromoting PEMT activity (111), and another study found that betaine stimulates apoB gene expression to form more VLDL (112).

甜菜碱处理可以恢复合成和氧化之间的不平衡,有助于减少脂肪堆积(97-99)。Song 和他的同事们发现,增加的肝 AMP活化蛋白激酶活性(AMPK)可能是机制性的(98)。AMPK 既是主要的细胞能量传感器,又是重要的代谢稳态调节剂,实际上,AMPK 控制着许多基因,如甾醇调节元件结合蛋白1c (SREBP-1c)、乙酰辅酶 a 羧化酶(ACC)和脂肪酸合酶(FAS)。活化的 AMPK 可以通过调节这些基因的表达来抑制脂肪酸合成和促进脂肪酸氧化。甜菜碱可以增加 AMPK 的磷酸化,进而抑制 ACC 的活性以及 SREBP-1c 和 FAS 的表达(98)。这一结果支持了 AMPK 可以直接磷酸化 Ser372位点 SREBP-1c 和 SREBP-2以抑制其活性从而减少饮食诱导的胰岛素抵抗小鼠(101)的脂肪生成和脂质积累的另一项研究的发现。此外,激活 AMPK 促进葡萄糖摄取通过改善葡萄糖转运子4型(GLUT-4)易位,这些发现表明对胰岛素抵抗(102)有益的影响。关于 AMPK 激活的机制,在正常条件下改变细胞中的 AMP: ATP 比例可激活 AMPK (103)。然而,肝脏 AMPK 的激活可以通过脂联素(104,105)独立于 AMP: ATP 比例发生。有趣的是,在 Song 的另一项研究中,甜菜碱可以恢复 NAFLD 异常的脂肪细胞因子水平,并且可以上调脂联素和下调脂肪细胞中的瘦素和抵抗素,从而减轻脂肪细胞因子脂质代谢失调。甜菜碱的类似作用也得到了另一项体外人类脂肪细胞研究(106)的支持。这些结果表明,脂联素的上调可能有助于 AMPK 的磷酸化(107)。此外,因为这些脂肪因子在炎症中起作用,这种正常化过程是抗炎症的(106)。除了激活 AMPK 外,甜菜碱处理还可能影响其他脂质代谢相关因子。早期的研究表明,甜菜碱可以通过降低过氧化物酶体增殖物激活受体 α (ppar)甲基化(108)来减少载脂蛋白B 基因缺陷小鼠甘油三酯的积累。在另一项研究中,甜菜碱通过抑制 FOXO-1与 ppar 启动子的结合来抑制 ppar 的转录活性,从而减少脂肪的积累(109)。在最近的一项研究中,当甜菜碱恢复脂肪酸氧化抑制时,不仅 ppar 上升,而且肝X受体(lxr)也上升。虽然甜菜碱如何激活 lxr 的机制尚不清楚,但它可能与一种与 sam- 相关的酶 PRMT-3有关,这种酶可以直接增加 lxr 的活性(38)。此外,在顺铂引起的肾毒性研究中,甜菜碱通过抑制肾脏硫代巴比妥酸-反应性物质的活化来抑制脂质过氧化,这种活化主要由氧化应激(110)引起。甜菜碱处理除了改变脂肪的合成和氧化外,还可以改善脂质的转运。一项研究发现,甜菜碱维持肝脏 SAM: SAH 比例,通过促进 PEMT 活性(111)来促进磷脂酰胆碱合成和正常化极低密度脂蛋白(VLDL)的产生,另一项研究发现,甜菜碱刺激 apoB 基因表达形成更多的 VLDL (112)。

With respect to glucose metabolism, studies have demonstrated that insulin resistance is associated with inflammation (113114). Morgan and colleagues discovered that betaine supplementation could directly act upon the insulin pathway to improve NAFLD (10). A similar phenomenon has been found in another study of type 2 diabetes (12). In these studies, betaine significantly reduced ser473-phosphorylated PKB/Akt levels, but it increased IRS-1 phosphorylation and thr308-phosphorylated PKB/Akt levels. The PKB/Akt regulates systemic and cellular metabolism, mainly by mediating cell proliferation, differentiation, and survival, and it is required for insulin signaling (115116). Then, thr308-phosphorylated PKB/Akt could restrict FOXO-1 and glycogen synthase kinase-3α activities (115). The former can decrease the expression levels of phosphoenolpyruvate carboxy kinase to reduce hepatic gluconeogenesis, whereas the latter can increase glycogen synthesis (117118). To verify whether betaine can directly initiate PKB/Akt, the authors used a PI3K inhibitor, wortmannin, and found it hard to detect activated PKB/Akt; these results suggest that betaine may directly enhance IRS-1 phosphorylation rather than directly activate PKB/Akt (10). The mechanism of how betaine enhances IRS-1 phosphorylation to improve insulin resistance remains unclear. However, Iwasaki and colleagues recently reported that PRMT-1 can methylate heterogeneous nuclear ribonucleoprotein (hnRNPQ) and may be involved in insulin signaling (119121). Mechanistically, PRMT-1 can catalyze the addition of a methyl group from SAM to hnRNPQ; this process results in internalization and lasting insulin receptor activation. Notably, SAM concentrations are associated with betaine. Therefore, these evidences speculated that betaine could improve the available SAM to generate more methylation hnRNPQ via PRMT-1 and thus PKB/Akt activation. Besides IRS-PKB/Akt signaling pathway, Chen and colleagues found that betaine treatment could reduce the protein levels of X-box-binding protein-1, an endoplasmic reticulum (ER) stress-related protein; this reduction is likely to enhance p38–MAPK and mammalian target of rapamycin activities and ultimately reduce hepatic gluconeogenesis and insulin resistance (89). Therefore, we conclude that betaine exerts its anti-inflammatory effects via restoring energy metabolism. These main metabolic pathways and key factors mediated by betaine treatment in chronic inflammation are shown in Table ​Table22.

关于葡萄糖代谢,研究表明胰岛素抵抗与炎症有关(113,114)。Morgan 和他的同事发现甜菜碱补充可以直接作用于胰岛素通路以改善 NAFLD (10)。在另一项关于2型糖尿病的研究中也发现了类似的现象。在这些研究中,甜菜碱显著降低了 ser473磷酸化 PKB/Akt 水平,但增加了 IRS-1磷酸化和308磷酸化 PKB/Akt 水平。蛋白激酶 b/akt 主要通过调节细胞的增殖、分化和存活来调节全身和细胞的代谢,它是胰岛素信号传导所必需的(115,116)。Thr308- 磷酸化 PKB/Akt 可抑制 FOXO-1和糖原合成酶激酶 -3活性(115)。前者可以降低磷酸烯醇式丙酮酸的表达水平,以减少肝糖异生,而后者可以增加糖原的合成(117,118)。为了验证甜菜碱是否可以直接启动 PKB/Akt,作者使用了 PI3K 抑制剂 wortmannin,发现很难检测活化的 PKB/Akt,这些结果表明甜菜碱可以直接促进 IRS-1的磷酸化,而不是直接激活 PKB/Akt (10)。甜菜碱如何增强 IRS-1磷酸化改善胰岛素抵抗的机制尚不清楚。然而,岩崎和他的同事最近报道 PRMT-1可以甲基化异质性核核糖核蛋白(hnRNPQ) ,可能参与胰岛素信号转导(119-121)。机制上,PRMT-1可以催化 SAM 中甲基的添加到 hnRNPQ 中; 这个过程导致了内在化和持久的胰岛素受体激活。值得注意的是,SAM 的浓度与甜菜碱有关。因此,这些证据推测甜菜碱可能通过 PRMT-1改善 SAM 产生更多的甲基化 hnRNPQ,从而激活 PKB/Akt。除了 IRS-PKB/Akt 信号通路外,Chen 和他的同事们发现甜菜碱处理可以降低 x-box 结合蛋白-1的蛋白质水平,这是一种与内质网应激相关的蛋白质,这种降低可能会增强 p38-MAPK 和哺乳动物雷帕霉素靶蛋白的活性,最终降低肝糖异生和胰岛素抵抗(89)。因此,我们认为甜菜碱通过恢复能量代谢发挥抗炎作用。在慢性炎症中甜菜碱介导的这些主要代谢途径和关键因子如表22所示。

Table 2

表二

Main metabolic pathways and genes/proteins influenced by betaine treatment in inflammation diseases.

甜菜碱对炎症疾病主要代谢途径及基因/蛋白的影响。

Results 结果Main metabolic pathway 代谢途径Gene/protein 基因/蛋白质Function of gene/protein 基因/蛋白质的功能Reference参考资料
Lipid metabolism↑ 脂质代谢AMPK pathway↑ AMPK 通路ACC↑ ACC ↑Fatty acid synthesis 脂肪酸合成
FAS↑ 雌雄同体Fatty acid synthesis 脂肪酸合成(98100101)
SREBP-1c↑ SREBP-1c ↑Fatty acid synthesis 脂肪酸合成
Others 其他PPARα↑, PPARγ↑ 雌激素Fatty acid oxidation 脂肪酸氧化(108109)
Fatty acid oxidation 脂肪酸氧化
LXRα↑ Lxr ↑Fatty acid oxidation 脂肪酸氧化(89)
TBARS↓ 4. t bar ↓Lipid peroxidation 脂质过氧化(110)
Apo B↑ Apo b ↑Cholesterol transport 胆固醇运输(111122)
Glucose metabolism↑ 葡萄糖代谢↑IRS-1/Akt pathway↑ IRS-1/Akt ↑通路IRS-1↑Insulin sensitivity 胰岛素敏感性(1012123124)
FOXO-1↓ 1↓Gluconeogenesis 糖异生作用
GSK3α↓ 3↓Inhibits glycogen synthesis 抑制糖原合成
Others 其他XBP-1↓ 1↓Gluconeogenesis 糖异生作用(89125)
GLUT-4↑Glucose transport 葡萄糖转运(102)

The upward arrows indicate promotion.

向上的箭头表示晋升。

The downward arrows indicate inhibition.

向下箭头表示抑制。

Betaine Mitigates ER Stress and Apoptosis

甜菜碱缓解内质网应激与细胞凋亡

Endoplasmic reticulum (ER) stress is caused by the abnormal assembly of proteins, as either misfolded or unfolded proteins, in the ER lumen (126). Various proteins, such as C/EBP homologous protein (CHOP) and glucose-regulated protein 78 (GRP78), are involved in ER stress, and both of these proteins are ER stress markers (127). Massive ER stress is undesirable and leads to cell apoptosis. Apoptosis is a type of cell death, and takes part in the pathogenesis of inflammatory diseases (128). Although apoptosis has extrinsic and intrinsic pathways, the final process is completed by caspase family proteins, especially caspase-3 (129).

内质网应激是由于蛋白质在内质网腔内的异常组装引起的,如错误折叠或未折叠的蛋白质。各种蛋白质如 C/EBP 同源蛋白(CHOP)和葡萄糖调节蛋白78(GRP78)参与了 ER 应激,这两种蛋白质都是 ER 应激标记物(127)。大量内质网应激是不受欢迎的,并导致细胞凋亡。细胞凋亡是细胞死亡的一种类型,参与了炎症性疾病的发病过程(128)。虽然细胞凋亡有外在途径和内在途径,但最终的过程是由 caspase 家族蛋白完成的,特别是 caspase-3(129)。

As mentioned, betaine can directly influence the homocysteine pool, and it has been reported that hyperhomocysteine can induce misfolded proteins, ultimately leading to ER stress (70). According to the research by Cheng, betaine can stabilize homocysteine levels and inhibit GRP78 and CHOP levels as well as cell death (130). Likewise, in another study, betaine inhibited both GRP78 and CHOP and reduced JNK activation (107). Interestingly, the JNK pathway can directly phosphorylate multiple IRS-1 sites, including serine-307. These modifications prevent insulin-stimulating IRS-1 tyrosine phosphorylation, which leads to insulin resistance (10). In addition to ER stress, betaine also inhibits apoptosis. In a recent study of rheumatoid arthritis synovial fibroblasts, Gaur and colleagues found that transcription factor-3 (ATF-3), an apoptosis-related molecule, is downregulated by betaine (131). In addition, betaine can inhibit caspase family proteins. In an in vitro study, adding adenosine to hepatocytes increased hepatic SAH levels and caspase-3 activity, both of which would be inhibited by betaine treatment (132). The inhibition of caspase-3 by betaine is also found in cisplatin-induced nephrotoxicity (110). Furthermore, betaine significantly reduced caspase-8, caspase-9, and caspase-3/7 activity in human corneal epithelial cells and MDCK cells under hyperosmotic stress (28133). Thus, we would like to believe that the mitigation of ER stress and apoptosis by betaine is essential to its anti-inflammatory effects.

甜菜碱可直接影响同型半胱氨酸库,有研究表明,高同型半胱氨酸可引起蛋白质错误折叠,最终导致内质网应激(70)。根据 Cheng 的研究,甜菜碱可以稳定同型半胱氨酸水平,抑制 GRP78和 CHOP 水平以及细胞死亡(130)。同样,在另一项研究中,甜菜碱抑制 GRP78和 CHOP,并降低 JNK 活性(107)。有趣的是,JNK 途径可以直接磷酸化多个 IRS-1位点,包括丝氨酸 -307。这些修饰阻止胰岛素刺激的 IRS-1酪氨酸磷酸化,从而导致胰岛素抵抗(10)。甜菜碱除内质网应激外,还抑制细胞凋亡。在最近一项关于类风湿性关节炎滑膜成纤维细胞的研究中,Gaur 和他的同事发现转录因子3(ATF-3) ,一种与细胞凋亡相关的分子,被甜菜碱(131)下调。此外,甜菜碱还能抑制 caspase 家族蛋白。在体外研究中,向肝细胞中添加腺苷可以提高肝脏 SAH 水平和 caspase-3活性,而甜菜碱处理可以抑制这两种活性。在顺铂所致的肾毒性(110)中也发现甜菜碱对 caspase-3的抑制作用。此外,甜菜碱还能显著降低高渗胁迫下人角膜上皮细胞和 MDCK 细胞 caspase-8、 caspase-9和 caspase-3/7的活性(28,133)。因此,我们愿意相信甜菜碱缓解内质网应激和细胞凋亡对其抗炎作用是必不可少的。Go to: 去:

Applications of Betaine in Human Diseases

Go to: 去:

甜菜碱在人类疾病中的应用

Recently, the effects of natural and nontoxic substances on human diseases have attracted considerable attention. Researches have shown that betaine has beneficial effects in various human diseases, such as obesity, diabetes, cancer, and Alzheimer’s disease (134141). Obesity results from excessive fat accumulation and has potentially negative effects on health. Obesity can lead to various secondary diseases, such as NAFLD. In animal studies, dietary betaine has been demonstrated to positively affect body fat (142143). However, few studies have focused on the effect of betaine on human obesity, and some of the results are contradictory. The current studies show that plasma betaine concentrations are inversely correlated with body fat percentages in adults; subjects with higher plasma betaine concentrations tended to have better fat profiles and distributions (134135). In a recent study, Gao and colleagues found that this positive correlation between plasma betaine concentrations and a better body composition existed in only males (144). Although this area deserves attention, there are few studies exploring the influence of betaine supplementation on obesity. In the studies of Schwab and Favero, betaine supplementation did not affect body composition (145146). However, in another study from Gao and colleagues, a large general population was analyzed, and a higher betaine intake was correlated with a better body composition (147). Similarly, other studies show that plasma betaine concentrations are inversely associated with human NAFLD, but the results of betaine supplementation are up for debate (148152). Thus, in order to get the reliable result, more studies need to focus on this area from now on. In addition, many animal studies have shown that betaine is closely linked with diabetes (12153154). Diabetes leads to hyperglycemia due to impaired glucose metabolism (155). Different from its role in obesity, plasma betaine concentration is a poor predictor for diagnosing diabetes in humans (137156157). Nevertheless, plasma betaine concentration is likely linked with secondary diseases of diabetes, such as microangiopathy (158). Studies have shown that abnormal urinary betaine excretion is closely associated with diabetes (136138), but its diagnostic value is lower than that of other substances, such as choline and DMG (159). Currently, only one study has investigated the effect of betaine supplementation on diabetes (160). Therefore, to identify whether betaine supplementation is effective, more systematic studies will be needed in the future. Various human studies have found that in addition to its association with metabolic diseases, betaine intake is associated with cancers, such as breast cancer, lung cancer, liver cancer, colorectal cancer, and nasopharyngeal carcinoma (139140161163). In these studies, a higher betaine intake resulted in a lower risk of cancer. Furthermore, research has suggested that cancer incidence could be decreased by 11% by consuming choline plus betaine (100 mg/day) (164). However, in some studies, contradictory results have been found (165166). For example, Lee and colleagues found no association between colorectal cancer and betaine intake (165). So far, most of these have been case–control studies; to obtain reliable results, placebo-controlled intervention trials and prospective studies will be needed. Recently, a study has shown that betaine intervention could restore hyperhomocysteine, which is a hallmark of Alzheimer’s disease (141), and attenuate the inflammatory reaction in Alzheimer’s disease patients (167). This finding further extended the range of betaine applications in human diseases.

近年来,天然和无毒物质对人类疾病的影响引起了人们的广泛关注。研究表明,甜菜碱对各种人类疾病有益,如肥胖症、糖尿病、癌症和阿尔茨海默病(134-141)。肥胖是由于脂肪堆积过多,对健康有潜在的负面影响。肥胖可导致各种继发性疾病,如 NAFLD。在动物研究中,食用甜菜碱已被证明对身体脂肪有积极影响(142,143)。然而,很少有研究关注甜菜碱对人类肥胖的影响,有些结果是矛盾的。目前的研究表明,血浆甜菜碱浓度与成年人体脂肪百分比呈负相关; 血浆甜菜碱浓度较高的受试者往往有较好的脂肪剖面和分布(134,135)。在最近的一项研究中,Gao 和他的同事们发现,血浆甜菜碱浓度与更好的身体成分之间存在正相关性,这种正相关性只存在于男性身上(144)。虽然这一领域值得关注,但是很少有研究探讨甜菜碱补充剂对肥胖的影响。在 Schwab 和法维罗的研究中,添加甜菜碱不影响身体组成(145,146)。然而,在高和他的同事的另一项研究中,研究人员分析了大量的普通人群,发现摄入较高的甜菜碱与较好的身体成分相关(147)。同样,其他研究表明,血浆甜菜碱浓度与人类非酒精性脂肪肝呈负相关,但补充甜菜碱的结果值得商榷(148-152)。因此,为了得到可靠的结果,今后需要对这一领域进行更多的研究。此外,许多动物研究表明甜菜碱与糖尿病密切相关(12,153,154)。糖尿病由于糖代谢受损而导致高血糖(155)。与其在肥胖症中的作用不同,血浆甜菜碱浓度是人类诊断糖尿病的一个较差的预测因子(137,156,157)。然而,血浆甜菜碱浓度可能与继发性糖尿病疾病,如微血管病变(158)。研究表明,尿中甜菜碱排泄异常与糖尿病密切相关(136-138) ,但其诊断价值低于其他物质,如胆碱和 DMG (159)。目前,只有一项研究调查了甜菜碱补充剂对糖尿病的影响(160)。因此,为了确定甜菜碱补充剂是否有效,今后还需要进行更系统的研究。各种人体研究发现,除了与代谢性疾病有关,甜菜碱摄入还与癌症有关,如乳腺癌、肺癌、肝癌、大肠癌和鼻咽癌(139,140,161-163)。在这些研究中,摄入较高的甜菜碱可以降低患癌症的风险。此外,研究表明,摄入胆碱加甜菜碱(100毫克/天)(164)可使癌症发病率降低11% 。然而,在一些研究中,发现了相互矛盾的结果(165,166)。例如,Lee 和他的同事发现大肠癌和甜菜碱摄入量之间没有联系。到目前为止,这些研究大部分是病例对照研究; 为了获得可靠的结果,需要安慰剂对照干预试验和前瞻性研究。最近,一项研究表明,甜菜碱干预可以恢复高同型半胱氨酸,这是阿尔茨海默病(141)的一个标志,并减轻阿尔茨海默病患者(167)的炎症反应。这一发现进一步扩大了甜菜碱在人类疾病中的应用范围。

In summary, despite some contradictory results, we propose that betaine may have an application in treatment or ameliorating symptoms of various huaman inflammatory diseases because of betaine’s significant anti-inflammatory effects (168). Notably, human diseases are undoubtedly more complex than animal disease models; therefore, to take advantage of the beneficial effects of betaine, researchers should continue to explore its mechanism and effects in humans.

总之,尽管有一些相互矛盾的结果,我们认为甜菜碱可能在治疗或改善各种花蔓炎症性疾病的症状的应用,因为甜菜碱具有显著的抗炎作用(168)。值得注意的是,人类疾病无疑比动物疾病模型更复杂; 因此,为了利用甜菜碱的有益作用,研究人员应继续探索其在人类中的机制和作用。Go to: 去:

Conclusion

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总结

In conclusion, this review discusses the major physiological role of betaine as an osmoprotectant and a methyl group donor, as well as the anti-inflammatory effects of betaine in various diseases. These effects are primarily associated with protecting SAA metabolism from oxidative stress, inhibiting NF-κB and NLRP3 inflammasome activity, regulating energy metabolism, and mitigating ER stress and apoptosis (Figure ​(Figure2).2). Although the data from animal experiments are compelling, the clinical situation appears to be much more complex than originally thought. For example, despite various animal studies reporting the effects of betaine supplementation and some mechanisms, human studies have shown contradictory results. Future studies should focus on both animal and clinical experiments to reduce errors from separate experiment types and to ensure the medicinal value of betaine. More importantly, it is worthwhile to further investigate betaine because its significant anti-inflammatory effects could be beneficial for treating inflammatory diseases.

本文综述了甜菜碱作为渗透调节剂和甲基供体的主要生理作用,以及甜菜碱在各种疾病中的抗炎作用。这些作用主要与保护 SAA 代谢免受氧化应激、抑制 nf-b 和 NLRP3炎症活性、调节能量代谢、减轻 ER 应激和细胞凋亡有关(图2)。2).尽管动物实验的数据令人信服,但临床情况似乎比最初想象的要复杂得多。例如,尽管各种动物研究报告了甜菜碱补充剂的效果和一些机制,但人类研究显示出相互矛盾的结果。今后的研究重点应放在动物实验和临床实验上,以减少不同实验类型的误差,保证甜菜碱的药用价值。更重要的是,甜菜碱具有明显的抗炎作用,有利于治疗炎症性疾病,值得进一步研究。

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Figure 2 图2

Primary anti-inflammatory mechanisms of betaine. First, betaine can alter various sulfur amino acid (SAA) concentrations via protecting SAA metabolism from oxidative stress. Second, betaine can inhibit IKK, MAPKs, HDAC3, and Toll-like receptor-4 (TLR-4) activities to downregulate the nuclear factor- κB (NF-κB) pathway and pro-inflammatory genes transcription. Third, betaine can reduce the expression levels of NLRP3 inflammation components (pro-caspase-1, ASC, and NLRP3) and inhibit the FOXO-1-induced NLRP3 inflammasome via enhancing the IRS/Akt pathway. Fourth, betaine significantly increases activated AMPK, restores adipokines that can activate AMPK, and activates other lipid metabolism-related factors to regulate lipid metabolism. Fifth, on the one hand, betaine increases phosphorylated IRS, which phosphorylates Akt at threonine 308, to improve glucose metabolism. On the other hand, betaine can influence other glucose metabolism-related factors to improve glucose metabolism. Sixth, betaine can inhibit caspase-3 to reduce apoptosis and repair endoplasmic reticulum (ER) stress. Akt, protein kinase B; AMPK, AMP-activated protein kinase; FOXO-1, forkhead box O1; TXNIP, thioredoxin-interacting protein; ROS, reactive oxygen species; IKK, nuclear factor-inducing kinase/IκB kinase; MAPKs, mitogen-activated protein kinases; HDAC3, histone deacetylases 3. SAM, S-adenosyl-L-methionine; SAH S-adenosyl-L-homocysteine; GSH, glutathione; Met, methionine; Cys, cysteine.

甜菜碱抗炎机制的初步研究。首先,甜菜碱可以通过保护 SAA 代谢免受氧化应激的影响而改变各种含硫氨基酸的浓度。其次,甜菜碱可抑制 IKK、 mapk、 HDAC3和 toll 样受体4(TLR-4)活性,下调核因子 -b (nf- b)通路和促炎基因转录。再次,甜菜碱可以通过增强 IRS/Akt 通路,降低 NLRP3炎症成分(caspase-1、 ASC 和 NLRP3)的表达水平,抑制 foxo-1诱导的 NLRP3炎症体。第四,甜菜碱显著增加活化的 AMPK,恢复能激活 AMPK 的脂肪因子,并激活其他与脂质代谢相关的因子来调节脂质代谢。第五,一方面,甜菜碱增加了磷酸化的 IRS,它在苏氨酸308处磷酸化 Akt,以改善葡萄糖代谢。另一方面,甜菜碱可以影响其他与糖代谢相关的因子,从而改善糖代谢。第六,甜菜碱能抑制 caspase-3,减少细胞凋亡和修复内质网应激。Akt,蛋白激酶 b; AMPK,AMP活化蛋白激酶; FOXO-1,叉头盒 O1; TXNIP,硫氧还蛋白相互作用蛋白; ROS,活性氧类; IKK,核因子诱导激酶/i b 激酶; mapk,丝裂原活化蛋白激酶; HDAC3,组蛋白去乙酰化酶3。S-腺苷甲硫氨酸; S-腺苷-L-高半胱氨酸; 谷胱甘肽,谷胱甘肽; 蛋氨酸,蛋氨酸; 胱氨酸,半胱氨酸。Go to: 去:

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