Encyclopedia
Please note this is a comparison between Version 1 by Hongli Zheng and Version 4 by Catherine Yang.
Phlorotannins are a type of natural active substance extracted from brown algae, which belong to a type of important plant polyphenol. Phloroglucinol is the basic unit in its structure. Phlorotannins have a wide range of biological activities, such as antioxidant, antibacterial, antiviral, anti-tumor, anti-hypertensive, hypoglycemic, whitening, anti-allergic and anti-inflammatory, etc. Phlorotannins are mainly used in the fields of medicine, food and cosmetics. 间苯单宁是从褐藻中提取的一种天然活性物质，属于一种重要的植物多酚。间苯三酚是其结构的基本单位。间苯单宁具有广泛的生物活性，如抗氧化、抗菌、抗病毒、抗肿瘤、抗高血压、降血糖、美白、抗过敏和抗炎等。间苯单宁主要用于医药、食品和化妆品领域。
- phlorotannins
- extraction technology
- separation and purification
1. Applications in the Field of Medicine在医学领域的应用
Phlorotannins, as a role of plant polyphenols, based on its hydrophilic and hydrophobic moieties, can interact with plasma proteins in the blood by non-covalent interactions (e.g., multiple hydrogen bonding, electrostatic, and cation-根皮单宁作为植物多酚的一种作用，基于其亲水和疏水部分，可通过非共价相互作用（例如多重氢键、静电和阳离子π interactions) [1][2]. Based on phenol units, polyphenols have the innate ability to reduce and scavenge free radicals and have a high affinity for proteins through specific or non-specific interactions [3]. They can interact with several receptors, regulate signal transduction, regulate enzyme activity, inactivate microorganisms and cross-link biological macromolecules [4], which indicates broad application prospects in tissue engineering. In the same way as the tannins of terrestrial plants, these phenolic compounds are highly soluble in water, strongly bind to proteins, polysaccharides, and other biopolymers, chelate divalent metals and have a polymer structure. Polyphenolic compounds extracted from seaweeds are bioavailable. Polyphenolic compounds can be absorbed either directly in the upper digestive tract unchanged or in the lower intestine after being modified by the bacteria present there [5].
Related studies have shown that phlorotannins from brown seaweeds showed low toxicity in cell lines, microalgae, seaweed spores, plants, invertebrates, animals (fish, mice, rats, and dogs) and humans at a moderate dosage [6]. Mild side-effects were recorded in humans, fish and dogs. However, the safety and toxicity of phlorotannins in aquaculture fish, livestock and companion animals are limited. These findings can serve as a basis for developing these compounds into novel functional foods, animal feeds and drugs.
相互作用）与血液中的血浆蛋白相互作用[97，98]。基于苯酚单元，多酚具有减少和清除自由基的先天能力，并通过特异性或非特异性相互作用对蛋白质具有高亲和力[99]。它们可以与几种受体相互作用，调节信号转导，调节酶活性，灭活微生物并交联生物大分子[100]，这在组织工程中具有广阔的应用前景。与陆生植物的单宁相同，这些酚类化合物高度溶于水，与蛋白质、多糖和其他生物聚合物强烈结合，螯合二价金属并具有聚合物结构。从海藻中提取的多酚化合物具有生物利用度。多酚化合物可以直接在上消化道吸收，原封不动地被吸收，也可以在被存在的细菌修饰后被下消化道吸收[101]。
相关研究表明，中等剂量下，褐海藻中的根皮单宁在细胞系、微藻、海藻孢子、植物、无脊椎动物、动物（鱼、小鼠、大鼠和狗）和人类中表现出低毒性[102]。在人类，鱼类和狗中记录了轻微的副作用。然而，根皮单宁在水产养殖鱼类、牲畜和伴侣动物中的安全性和毒性有限。这些发现可以作为将这些化合物开发成新型功能性食品、动物饲料和药物的基础。
1.1. Cancer Prevention and Treatment癌症预防和治疗
Excessive oxidative stress can cause oxidative damage to intracellular biological macromolecules, promote abnormal gene expression and 过度的氧化应激会对细胞内生物大分子造成氧化损伤，促进异常基因表达和DNA structural changes and block vital signaling pathways between cells [7]. Brown algae polyphenols have good anticancer activity, and their mechanism of action is mainly manifested either directly as a pro结构变化，阻断细胞间的重要信号通路[107]。褐藻多酚具有良好的抗癌活性，其作用机制主要表现为促凋亡、抗增殖、抗转移或抗血管生成剂，或间接表现为抑制与肿瘤发生密切相关的氧化应激炎症网络[108]。褐藻多酚粗提取物的抗癌活性与纯化的分离成分有很大不同。在含有肉瘤异种移植物的小鼠模型中，埃科尔的体内抗肿瘤作用不仅由于其能够干扰半胱天冬酶-apoptotic, antiproliferative, anti-metastatic or anti-angiogenic agent, or indirectly by inhibiting the oxidative-stress inflammatory network closely related to tumorigenesis [8]. The anticancer activity of brown algae polyphenol crude extracts differs greatly from purified isolated components. In mouse models containing sarcoma xenografts, the in vivo antitumor effect of eckol was shown not only due to its ability to interfere with the expression of caspase-3, caspase，半胱天冬酶-9, Bcl-2 and Bax genes, but also due to its ability to inhibit epidermal growth factor receptor (EGFR) expression. Thus, in addition to its antiproliferative properties, eckol exerts antitumor activity by stimulating the host immune response. Imbs et al. [9] found that among three different seaweeds, Fucus evanescens, Laminaria cichorioides and Costaria costata, the former with 60% ethanol extracts have highest content of polyphenols (，Bcl-2和Bax基因的表达，而且还由于其抑制表皮生长因子受体（EGFR）表达的能力。因此，除了其抗增殖特性外，eckol 还通过刺激宿主免疫反应来发挥抗肿瘤活性。Imbs等[109]发现，在3种不同的海藻中，墨角藻、海带海带和海苔属中，前者乙醇提取物含量最高（干物质为10.1% dry matter), showed the strongest inhibitory effect on ），对DLD-1 and HT-29 colorectal adenocarcinoma cell growth (67% and 63%).
Some studies have shown that, in the same way as plant phenolics, phlorotannins tend to degrade during their passage throughout the gastrointestinal tract, and only a small portion will reach the intestinal lumen intact and become bio-accessible for further absorption [10]. 和HT-29结直肠腺癌细胞生长的抑制作用最强（67%和63%）。
一些研究表明，与植物酚类物质一样，根皮单宁在整个胃肠道中通过时往往会降解，只有一小部分会完整地到达肠腔并变得生物可进一步吸收[89]。根据According to the work of Ahn et al. [11], carried out in xenograft mice models implanted with n等人的工作[110]，在植入SKOV3 ovarian cancer cells, the oral a卵巢癌细胞的异种移植小鼠模型中进行，口服dministration of dieckol (300 mg/kg/week) was even more effective than cisplatin (9 mg/kg/week) at suppressing the tumor growth without showing any liver or kidney toxicity, while the cisplatin-treated mice revealed increased blood urea nitrogen and serum creatinine which are indicative of kidney dysfunction. ieckol（300mg / kg /周）甚至比顺铂（9mg / kg /周）更有效地抑制肿瘤生长而不显示任何肝或肾毒性，而顺铂处理的小鼠显示血尿素氮和血清肌酐增加，这表明肾功能障碍。Dieckol, derived from edible brown alga 来源于食用褐藻Ecklonia cava, can significantly enhance the inhibition of tumor growth by cisplatin with lower weight loss and kidney damage in a mouse model [12]. It also indicated that brown algae phlorotannins may improve the efficacy of platinum drugs for ovarian cancer by enhancing cancer cell apoptosis via the ，在小鼠模型中可显着增强顺铂对肿瘤生长的抑制，同时降低体重减轻和肾脏损伤[111]。褐藻根皮单宁可能通过ROS/Akt/NFκB pathway and reduce nephrotoxicity by protecting against normal kidney cell damage.
途径增强癌细胞凋亡，提高铂类药物对卵巢癌的疗效，并通过防止正常肾细胞损伤来降低肾毒性。
1.2. Treatment of Neurodegenerative Diseases神经退行性疾病的治疗
The phenomenon of excitatory toxicity caused by glutamate is associated with the pathophysiology of a variety of central nervous system diseases, which can lead to neuronal dysfunction, degeneration and apoptosis [13][14][15]. Brown algae polyphenols have been found to protect brain cells from glutamate excitatory toxicity through multimodal action. The mechanism of action is as follows: the ability to inhibit central nervous system (谷氨酸引起的兴奋性毒性现象与多种中枢神经系统疾病的病理生理学有关，可导致神经元功能障碍、退化和细胞凋亡[112，113，114]。已经发现褐藻多酚通过多模式作用保护脑细胞免受谷氨酸兴奋性毒性。作用机制如下：抑制中枢神经系统（CNS)-related enzymes (acetylcholinesterase and butyrylcholinesterase, monoaminoxidase, ）相关酶（乙酰胆碱酯酶和丁酰胆碱酯酶，单氨基氧代酶，β-secretase, tyrosinase); Regulation of neuronal receptors; Regulation of the signaling pathways and neuroinflammation associated with oxidative stress-mediated neuronal cell death [16].
分泌酶，酪氨酸酶）的能力;调节神经元受体;与氧化应激介导的神经元细胞死亡相关的信号通路和神经炎症的调节[2]。
Yang et al. [17] demonstrated that phloroglucinol, the basic unit of brown algae polyphenols, regulates synaptic plasticity. With a decrease in dendritic spine density and synaptic protein levels, cognitive dysfunction in 等人[115]证明间苯三酚是褐藻多酚的基本单位，调节突触可塑性。随着树突棘密度和突触蛋白水平的降低，5XFAD mouse models was alleviated. 小鼠模型中的认知功能障碍得到缓解。口服后，还观察到After oral administration of it, a significant decrease in the number of Aβ plaques and the level of the β斑块的数量和BACE-1 protein was also observed. In addition, resorcinol prevents lipid peroxidation, slows the reactivation of glial cells, and reduces the release of pro-inflammatory cytokines in 5XFAD mice.
Polyphenols such as phlorotannins must cross the physical barrier of the CNS to exert a neuroprotective effect: the blood–brain barrier (蛋白水平的显着降低。此外，间苯二酚可防止脂质过氧化，减缓神经胶质细胞的再活化，并减少5XFAD小鼠中促炎细胞因子的释放。
根皮单宁等多酚必须穿过中枢神经系统的物理屏障才能发挥神经保护作用：将循环血液与脑细胞外液分离的血脑屏障（BBB) that separates the circulating blood from the brain extracellular fluid. Phlorotannin’s action through the ）。根皮单宁通过BBB on gamma aminobutyric acid type A (GABAA)-benzodiazepine receptors has been demonstrated. 对γ氨基丁酸A型（GABAA）-苯二氮卓受体的作用已被证明。Dieckol [18] and [116]和eckol [19] have been effectively shown to successfully penetrate the brain by the [117]已被有效地证明可以通过BBB via still unknown transportation mechanisms.
通过未知的运输机制成功穿透大脑。
1.3. Development of Novel Antifungal Drugs新型抗真菌药物的开发
Polyphenolic compounds have a universal inhibitory effect on microorganisms [6]. On the one hand, phlorotannins block the synthesis of dimorphic complexes in fungal cells, resulting in an altered appearance and surface adhesion properties of Pseudomonas, thereby reducing the toxicity and ability of pathogenic fungi to invade host cells. On the other hand, phlorotannins induce reactive oxygen species (多酚化合物对微生物具有普遍的抑制作用[102]。一方面，间苯单宁阻断真菌细胞中二态复合物的合成，导致假单胞菌的外观和表面粘附性能改变，从而降低病原真菌侵入宿主细胞的毒性和能力。另一方面，根皮单宁诱导活性氧（ROS) production and trigger early apoptosis, leading to activation of the ）产生并触发早期细胞凋亡，导致CaMCA1 gene and destruction of cell membranes in Candida albicans. These inhibitory effects reflect the potential of phlorotannins as a novel antifungal drug [20] [21][22].
基因的激活和白色念珠菌细胞膜的破坏。这些抑制作用反映了间苯单宁作为新型抗真菌药物的潜力[44，118，119]。
Lopes et al. [23] crushed the dried Fucus spiralis Linnaeus, degreased with n-hexane and extracted with acetone: water (等人[120]将干燥的墨角藻螺旋林奈压碎，用正己烷脱脂并用丙酮：水（7:：3). The extract is purified with cellulose and then washed with toluene. Then, the cellulose is washed with acetone: water (7:3) to obtain phlorotannins. These phlorotannins exhibit antifungal activity against Candida albicans, Aspergillus and Dermatophytes. The ）提取。提取物用纤维素纯化，然后用甲苯洗涤。然后，用丙酮：水（7：3）洗涤纤维素以获得间苯单宁。这些根皮单宁对白色念珠菌、曲霉菌和皮肤癣菌具有抗真菌活性。这些真菌的间苯单宁的MIC values of phlorotannins for these fungi range from 值范围为3.9 to 31.3 mg/mL.
At present, most of the antibacterial activity studies on brown seaweeds’ polyphenols are in vitro activity studies, and no pharmacokinetic analysis of polyphenols exerting antibacterial effects has been found.
至31.3mg / mL。
目前，褐海藻多酚的抗菌活性研究大多是体外活性研究，尚未发现多酚发挥抗菌作用的药代动力学分析。
1.4. Development of New Blood Pressure Lowering Drugs新降血压药物的开发
血管紧张素转换酶（Angiotensin-converting enzyme (ACE) is an ideal target for the treatment of diseases such as hypertension, heart failure, diabetes mellitus and hypertension. In the study of blood pressure-lowering activity of brown algae, it has been proved that brown algae such as Undaria pinnatifida, Scagassu）是治疗高血压、心力衰竭、糖尿病和高血压等疾病的理想靶标。在褐藻降血压活性的研究中，已经证明褐藻如榕、黄藻、日本海带、水疱墨角藻和梭藻含有降血压活性物质[121]。
从Kom, Laminaria japonica, Fbucus vesiculosus and Hizikia fusifarme contain blood pressure-lowering active substances [24].
乙醇提取物中分离的Dieckol isolated from the ethanol extract of Kombu is a non-competitive inhibitor against 是一种针对ACE I that induces the production of nitric oxide (NO) in 的非竞争性抑制剂，可诱导EA.hy926 cells and has no cytotoxic effect [25]. 细胞产生一氧化氮（NO），并且没有细胞毒性作用[85]。Ko et al. [26] extracted 6,6’-bisphenols from the 等人[122]从Ecklonia cava and studied its biological activity, finding that 中提取6，6'-双酚并研究其生物活性，发现ACE inhibitory activity was formed by the interaction of hydrogen bonds and Pi bonds between ACE and 6,6’-biphenol. The 6,6’-bisphenol significantly increased the content of NO by phosphorylation of nitric oxide synthase in human endothelial cells.
Until now, most of these 抑制活性是由ACE与6，6'-联苯酚之间的氢键和Pi键相互作用形成的。6，6'-双酚通过人内皮细胞中一氧化氮合酶的磷酸化显著增加了NO的含量。
到目前为止，大多数这些ACE inhibitory activities have been observed in vitro or in mouse model systems. Therefore, further research studies are needed in order to investigate their activity in human subjects. So far, there were no clinical studies of phlorotannins in patients with hypertension.
抑制活性已在体外或在小鼠模型系统中观察到。因此，需要进一步的研究来调查它们在人类受试者中的活性。到目前为止，还没有根皮单宁在高血压患者中的临床研究。
1.5. Anti-Diabetic and Anti-Obesity Potential抗糖尿病和抗肥胖潜力
In recent years, with the separation and identification of active ingredients in Laminaria japonica, Undaria pinnatifida, Scagassum and other brown algae, it has been proved that most brown algae contain hypoglycemic active substances [27]. Phlorotannins from the genus kombu exhibit anti-diabetic activity mainly through the inhibition of 近年来，随着海连、针叶海带、白藻等褐藻中活性成分的分离鉴定，证明大多数褐藻都含有降血糖活性物质[123]。来自海带属的根皮单宁主要通过抑制α-amylase, 淀粉酶、α-glucosidase, pancreatic lipase and aldose reductase (AR), which can promote the delay of carbohydrate and lipid digestion, followed by reducing postprandial plasma glucose levels and overall body weight, thereby helping to prevent and improve metabolic disorders such as diabetes mellitus type 2 (T2DM) and obesity [28].
Phlorotannins isolated from methanol extracts of 葡萄糖苷酶、胰脂肪酶和醛糖还原酶（AR）来表现出抗糖尿病活性，这些酶可以促进碳水化合物和脂质消化的延迟，其次是降低餐后血浆葡萄糖水平和整体体重，从而有助于预防和改善代谢紊乱，如2型糖尿病（T2DM）和肥胖症[124]。
从Ecklonia stolonifera have inhibitory activity against 的甲醇提取物中分离的根皮单宁对α-glucosidase, which is attributed to the presence of rhizolutin 葡萄糖苷酶具有抑制活性，这归因于根唑仑素A, ，dieckol and 和7-rhizophericol [29]. 根瘤菌醇的存在[125]。Lee et al. [30] extracted a phlorotannin from the 等[126]以链脲佐菌素诱导的糖尿病小鼠为模型，从Ecklonia cava, modeled on streptozotocin-induced diabetic mice, and after feeding, blood samples were taken from the tail vein at 腔中提取根皮单宁，喂食后，在0, 、30, 60 and 120 min and the blood glucose amount was measured. It was found that it had strong inhibitory activity against α-glucosidase and α-amylase.
Further clinical studies have shown that the physiological effects of seaweed supplementation can reduce fasting blood glucose and two hours postprandial blood glucose levels in patients with type 、60和120分钟从尾静脉取血样，测量血糖量。发现其对α-葡萄糖苷酶和α-淀粉酶有较强的抑制活性。
进一步的临床研究表明，补充海藻的生理作用可降低2型糖尿病患者的空腹血糖和餐后2 diabetes (control: 小时血糖水平（对照：254.4 ± 22.8 mg/dL, seaweed supplementation: 203.1 ± 12.3 mg/dL) without affecting glycated hemoglobin levels [31]. ±22.8mg/dL，补充海藻：203.1±12.3mg/dL），而不影响糖化血红蛋白水平[127]。Shannon and 和Abu-ghannam [32] found that the daily supplementation of [128]发现，通过临床试验，每日补充Undaria pinnatifida balanced the blood glucose levels in patients with type 可以平衡2 diabetes mellitus by clinical trial.
A 型糖尿病患者的血糖水平。
一项为期24-week randomized, double-blind, placebo-controlled crossover trial was conducted to investigate the effects of brown seaweeds’ polyphenols on 周的随机、双盲、安慰剂对照交叉试验，研究褐海藻多酚对超重或肥胖人群DNA damage and antioxidant activity in overweight or obese people [33]. A total of 损伤和抗氧化活性的影响[105]。共有80 participants (名参与者（BMI units: kg/单位：kg / m2 ≥ 25) aged 30–65 years consumed either a 400-mg capsule containing 100 mg seaweed (poly)phenol and 300 mg maltodextrin or a 400-mg maltodextrin placebo control capsule daily for an 8-wk period. Consumption of the seaweed (poly)phenols resulted in a modest decrease in DNA damage but only in a subset of the total population who were obese. There were no significant changes in C-reactive protein (CRP), antioxidant status or inflammatory cytokines.
岁）年龄在 30-65 岁之间每天服用含有 100 毫克海藻（多）苯酚和 300 毫克麦芽糊精的 400 毫克胶囊或 400 毫克麦芽糊精安慰剂对照胶囊，持续 8 周。食用海藻（多）酚导致DNA损伤适度减少，但仅在总人口中肥胖的一小部分。C反应蛋白（CRP）、抗氧化状态或炎性细胞因子无显著变化。
1.6. SARS Virus Inhibitors病毒抑制剂
Due to its multiple functions and necessary roles in viral replication and pathogenesis, cysteine proteases can be used as an ideal target for antiviral drugs. Among them, the master protease (半胱氨酸蛋白酶由于其在病毒复制和发病机制中的多种功能和必要作用，可作为抗病毒药物的理想靶标。其中，主蛋白酶（3CL) is a structural protein that affects the survival and reproduction of the virus by cutting the site of action of the polymer protein. The ）是一种结构蛋白，通过切割聚合物蛋白的作用位点来影响病毒的存活和繁殖。3CL protease is also an enzyme necessary for coronavirus replication, which is a target for potential anti-SARS蛋白酶也是冠状病毒复制所必需的酶，是潜在抗SARS药物的靶标。在从卡瓦埃克洛尼亚乙醇提取物中分离出的九种根皮单宁中，通过二苯醚连接的二氯醇表现出最有效的 drugs. Of the nine phlorotannins isolated from the ethanol extract of the Ecklonia cava, dieckol, which is connected by diphenyl ether, exhibits the most potent SARS-CoV inhibitory activity. In ad抑制活性。此外，dition, dieckol has the most potent inhibitory activity against cell-based 3CL, which is more potent than other phlorotannins’ derivatives and natural reference inhibitors. 对基于细胞的 3CL 具有最有效的抑制活性，它比其他间苯单宁衍生物和天然参比抑制剂更有效。Dieckol has a high association rate with proteins and forms strong hydrogen bonds with the catalytic binary of 与蛋白质具有很高的缔合率，并与 SARS-CoV 3CL (（Cys145 and和 His41) and consumes the lowest binding energy [34].
To explore the pharmacokinetics of brown macroalgal polyphenols during their antiviral activity, ）的催化二元形成强氢键，并且消耗最低的结合能[129]。
为了探索棕色大藻多酚在抗病毒活性期间的药代动力学，Gunaseelan et等人 al.[78] [35]评估了根单宁作为 evaluated the potential of root tannins as multiple-target protein antagonists necessary for SARS-CoV-2 replication. Top-ranked marine brown algal phlorotannins are difucol hexaacetate, diphlorethol pentaacetate, eckol hexaacetate and fucofuroeckol.
Based on the existing studies of 复制所需的多靶点蛋白质拮抗剂的潜力。排名靠前的海洋褐藻根皮单宁是六乙酸地夫考、五乙酸倍氮乙二醇、六乙酸埃科尔和岩藻呋喃酮。
基于对间苯单宁化合物的ADMET (（吸收、分布、代谢、排泄和毒性）特性的现有研究，已经清楚地理解了间苯单宁配体分子作为口服候选药物的生物利用度[78]。其次是首过代谢，与标准药物相比，肠血屏障的极性、水溶性和通透性达到足够的水平。此外，在限制下也观察到代谢反应和血脑屏障，除了根皮氧呋喃酚Absorption, Distribution, Metabolism, Excretion and Toxicity) characteristics of phlorotannins’ compounds, have clearly comprehended the bioavailability of the phlorotannin ligand molecules as an oral drug candidate [35]. Followed by the first-pass metabolism, polarity, aqueous solubility and permeability of the gut–blood barrier appeared at an adequate level as compared with standard drugs. Furthermore, the metabolic reaction and blood–brain barrier are also observed under limitation as per the standard volume, which can be seen in moderate levels in all of the ligands except phlorofucofuroeckol A and 和B, fucodiphloroethol ，岩藻二苯酚G, tetrafucol A, tetraphlorethol, fucotriphlorethol and diphlorethohydroxycarmalol.
，四夫酚A，四氯乙二醇，岩藻三酚和白膦羟卡马洛尔外，所有配体中都可以看到中等水平。
通过分析用于对抗Comparative studies of the route of administration were conducted by analyzing the results obtained from standard drugs used to combat COVID-19, such as remdesivir, ritonavir, favipiravir, lopinavir and hydroxychloroquine. Among them, hydroxychloroquine showed the highest human oral adsorption rate (about 91%), while the most commonly used remdesivir showed only 36% oral adsorption against 的标准药物（如瑞德西韦，利托那韦，法匹拉韦，洛匹那韦和羟氯喹）获得的结果，对给药途径进行了比较研究。其中羟氯喹对人体口服吸附率最高（约91%），而最常用的瑞德西韦对COVID-19. The dioxinodehydroeckol, diphlorethol, diphlorethol pentaacetate and difucol hexacetate manifested a higher degree of oral absorption (58.0, 58.05, 58.84, 47.30, respectively) as compared with standard remdesivir [36]. At the same time, diphlorethol pentaacetate (的口服吸附率仅为36%。与标准瑞德西韦相比，二氧乙二醇、双膦乙二醇、五乙酸二膦乙二醇和己醋酸地夫考酯的口服吸收程度更高（分别为58.0、58.05、58.84、47.30）[130]。同时，五乙酸倍苯乙二醇（70.56) had a higher ）在给定范围内（25至500）具有比标准瑞德西韦（仅6）更高的Madin-Darby canine kidney (MDCK) permeability within the given range (25 to 500) than standard remdesivir (just 6).
犬肾（MDCK）通透性。
1.7. Metabolomic Profiling Analysis of the Extract of Brown Seaweeds棕色海藻提取物的代谢组学分析分析
The majority of phlorotannin metabolites were found in samples collected at late time points (大多数根皮单宁代谢物是在晚期时间点（6–-24 h), indicating limited small intestinal absorption. Seaweed phlorotannins are metabolized and absorbed, predominantly in the large intestine, and there is a large inter-individual variation in their metabolic profile [37]. 小时）收集的样品中发现的，表明小肠吸收有限。间苯单宁主要在大肠中代谢和吸收，其代谢谱存在较大的个体间差异[131]。在上消化道中，膳食多酚充当许多酶的底物，它们受到葡萄糖苷酶（In the upper GI tract, dietary polyphenols act as substrates for a number of enzymes, and they are subjected to extensive metabolism by glucosidase enzymes, phase I enzymes (hydrolyzing and oxidizing) [38]. Thus, phlorotannin intake results in the formation of phase 期酶（水解和氧化）的广泛代谢[132]。因此，根皮单宁的摄入导致II conjugate metabolites (glucuronides, sulphates). Further transformations can occur in the colon, in which the enzymes of the gut microbiota act to breakdown complex polyphenolic structures to smaller units, which may also be absorbed and further metabolized in the liver [39].
In recent years, brown algae polyphenols have been a research hotspot in the field of marine compounds. However, there have been few studies into the metabolic changes following ingestion of brown algae extract. 期共轭代谢物（葡糖苷酸，硫酸盐）的形成。结肠可发生进一步转化，肠道微生物群的酶将复杂的多酚结构分解成更小的单位，这些多酚结构也可能在肝脏中被吸收并进一步代谢[133]。
近年来，褐藻多酚一直是海洋化合物领域的研究热点。然而，关于摄入褐藻提取物后的代谢变化的研究很少。Kim et al. [40] investigated the metabolic effects of a 等人[134]研究了食用12-week consumption of E周的E. cava polyphenol extracts (多酚提取物（seapolynol) in subjects exposed to moderate caloric intake and physical activity and with a body mass index (BMI) higher than 25 kg/）对暴露于适度热量摄入和体力活动且体重指数（BMI）高于25 kg / m的受试者的代谢影响2且低于 and lower than 30 kg/m30 公斤/米2. Urinary metabolomic profiling analysis showed that the levels of riboflavin, urocanic acid, 尿代谢组学分析显示，与安慰剂组相比，海多醇摄入组核黄素、尿酸、5-hydroxy-6-methoxyindole glucuronide and guanidino valeric acid were significantly increased in the seapolynol intake group compared with the placebo group. These findings suggest that the decreased body fat induced by the intake of seapolynol is related to an increase in the antioxidant effect of riboflavin.
羟基-6-甲氧基吲哚葡糖苷酸和胍基戊酸水平显著升高。这些发现表明，摄入海多醇引起的体内脂肪减少与核黄素抗氧化作用的增加有关。
2. Applications in the Food Sector在食品领域的应用
2.1. As a Functional Food against Hypercholesterolemia作为对抗高胆固醇血症的功能性食品
The main risk factor for coronary heart disease is excessive dietary cholesterol depletion, which, once arterial plaques form, can lead to fatal myocardial infarction, heart attack and cerebrovascular disease [41]. Currently, the intake of naturally active products can be used as a strategic therapy for the combined use of anti-hyperlipidemia drugs [42]. Studies have shown that algae compounds have the ability to bind dietary cholesterol, and brown algae have the ability to accelerate the excretion of cholesterol by the human body. Therefore, brown algae belong to a valuable food source of natural compounds that can be used to treat high cholesterol. A variety of brown algae species have shown the ability to lower blood lipid levels and total cholesterol [43].冠心病的主要危险因素是膳食胆固醇过度消耗，一旦形成动脉斑块，可导致致命的心肌梗死、心脏病发作和脑血管疾病[135]。目前，摄入天然活性产物可作为联合使用抗高脂血症药物的战略疗法[136]。研究表明，藻类化合物具有结合膳食胆固醇的能力，褐藻具有加速人体排泄胆固醇的能力。因此，褐藻属于可用于治疗高胆固醇的天然化合物的宝贵食物来源。多种褐藻物种已显示出降低血脂水平和总胆固醇的能力[137]。
Phlorotannins regulate serum lipid levels in most cases, reducing the risk of cardiovascular and cerebrovascular disease. The hypolipidemic effects of phlorotannins may also be associated with the antioxidant, anti-inflammatory and hepatoprotective activity of polyphenol compounds, thereby inhibiting fat-induced liver damage and ensuring lipid normalization [44][45]. 间苯单宁在大多数情况下调节血脂水平，降低患心脑血管疾病的风险。根皮单宁的降血脂作用也可能与多酚化合物的抗氧化、抗炎和保肝活性有关，从而抑制脂肪诱导的肝损伤并确保脂质正常化[138，139]。据报道，从水疱墨角藻和卡瓦埃克洛尼亚分离的Dieckol isolated from Fucus vesiculosus and Ecklonia cava has been reported to have the ability to inhibit 具有抑制HMG-CoA reductase, affecting cholesterol synthesis [46][47], thus demonstrating that phlorotannins have the same mode of action as statins.还原酶的能力，影响胆固醇合成[140，141]，从而证明间苯单宁具有与他汀类药物相同的作用方式。
2.2. As Food Antioxidants作为食品抗氧化剂
The special phenolic hydroxyl structure endows brown algae polyphenols with antioxidant activity [48]. The phenolic hydroxyl structure can provide hydrogen donors and scavenge a variety of reactive oxygen species (特殊的酚羟基结构赋予褐藻多酚抗氧化活性[142]。酚羟基结构可以提供供氢体并清除多种活性氧（ROS). On the one hand, the excited state oxygen molecules are reduced to the ground-state oxygen with lower activity, and the generation of oxygen free radicals is inhibited. On the other hand, as a free radical scavenger, brown algae polyphenol can combine with oxygen free radicals, reduce the activity of free radicals and hinder the chain-reaction of free radical scavenger [49]. The strength of the antioxidant effect of polyphenols is affected by the molecular structure and the number of hydroxyl groups, chain length and number of intramolecular hydrogen bonds [50][51]. Taking advantage of the antioxidant effects of brown algae polyphenols, it can also be used to treat degenerative diseases such as cardiovascular disease, diabetes, cancer, atherosclerosis and Alzheimer’s disease [52].）。一方面，激发态氧分子还原为活性较低的基态氧，抑制氧自由基的产生。另一方面，褐藻多酚作为自由基清除剂，可与氧自由基结合，降低自由基的活性，阻碍自由基清除剂的连锁反应[143]。多酚抗氧化作用的强弱受分子结构和羟基数、链长和分子内氢键数的影响[144，145]。利用褐藻多酚的抗氧化作用，也可用于治疗退行性疾病，如心血管疾病、糖尿病、癌症、动脉粥样硬化和阿尔茨海默病[146]。
Meng Tong [53] studied the effect of polyphenols from Laminaria japonica on the quality of emulsified intestines, and found that the brown algae polyphenols can reduce the content of carbonyl groups and the loss of sulfhydryl groups, and inhibit the oxidation of proteins [54]. In addition, when brown algae polyphenols are used to preserve oils and fats, they can act as antioxidants and color protection at the same time. Brown algae polyphenols can also undergo complex reactions with metal ions, thereby inhibiting the oxidation of food by a small amount of metal ions.孟彤[147]研究了海带多酚对乳化肠品质的影响，发现褐藻多酚能降低羰基的含量和巯基的损失，抑制蛋白质的氧化[148]。此外，当褐藻多酚用于保存油脂时，它们可以同时起到抗氧化剂和颜色保护的作用。褐藻多酚还可以与金属离子发生复杂的反应，从而抑制少量金属离子对食物的氧化。
2.3. As Food Preservatives作为食品防腐剂
褐藻多酚是一种兼具抗菌和抗氧化活性的提取物，可直接用于制备新型食用包装膜。研究表明，这种包装膜具有抗菌保存和防止物理损坏的功能，在食品储存和保存领域发挥了很大的作用[149]。从马尾藻中提取的低分子量根皮单宁会破坏副溶血性弧菌的细胞膜和细胞壁，导致细胞质渗漏和膜通透性解构。
Brown algae polyphenols are a kind of extract with both antibacterial and antioxidant activities, which can be directly used in the preparation of new edible packaging films. Studies have shown that this packaging film has the functions of antibacterial preservation and prevention of physical damage, and has played a great role in the field of food storage and preservation [55]. Low molecular weight phlorotannins extracted from Sargassum thunbergia damaged the cell membrane and cell wall of Vibrio parahaemolyticus, causing cytoplasm leakage and deconstruction of membrane permeability.
Shi [56] prepared nanoparticles embedded with algal polyphenols by the ion gel method, and found that the preservative obtained by this method had a better preservation performance and longer preservation time. Some phlorotannins derived from brown algae species have been studied in the application of antibacterial agents.
石[150]采用离子凝胶法制备了包埋有藻类多酚的纳米颗粒，发现该方法得到的防腐剂具有更好的保鲜性能和更长的保鲜时间。一些来自褐藻物种的根皮单宁已经在抗菌剂的应用中进行了研究。
2.4. As Pesticides作为杀虫剂
The
根皮单宁的杀幼虫作用由多种机制介导，包括直接抑制幼虫的沉降和/或存活以及调节细菌微污染物的生长，从而影响幼虫的沉降。从马尾藻中分离的根皮单宁在低浓度（25 larvicidal effects of phlorotannins are mediated by multiple mechanisms, includinμg direct inhibition of the settlement and/or survival of larvae and regulation of the growth of bacterial micropollutants, thereby affecting larval settling. Phlorotannins isolated from Sargassum inhibited the metamorphism of /mL）下抑制了33% of 的Ciona Savignyi and 和27% of 的Halocynthia roretzi at low concentrations (25 μg/mL). These findings suggest that phlorotannins can act as antifouling agents without causing damage to other organisms [57].
The larvicidal activities of phlorotannins in mosquitoes reported by Ravikumar et al. [58] and 等人[154]和Manilal et al. [59] suggest that they may be effective repellents. Phlorotannins have an effect on the larvae of marine invertebrates [60], suggesting that they are natural antifouling agents. Unlike heavy metals, which act as broad-spectrum toxins against both target and non-target marine organisms, the natural antifouling effect of phlorotannins is specific to target organisms.
等人[155]报道的根皮单宁在蚊子中的幼虫杀虫活性表明它们可能是有效的驱虫剂。根皮单宁对海洋无脊椎动物的幼虫有影响[156]，表明它们是天然防污剂。与作为广谱毒素对目标和非目标海洋生物的重金属不同，根皮单宁的天然防污作用是目标生物特有的。
3. Application in the Field of Cosmetics在化妆品领域的应用
3.1. Whitening and Beauty Effects美白和美容效果
酪氨酸酶是黑色素形成过程中的关键酶。通过在化妆品中添加酪氨酸抑制剂来抑制黑色素的形成，可以达到化妆品的美白效果。黑色素的产生始于酪氨酸氧化成多巴醌，多巴醌由酪氨酸酶（Tyrosinase is a key enzyme in the process of melanin formation. By adding tyrosine inhibitors to cosmetics to inhibit the formation of melanin, the whitening effect of cosmetics can be achieved. Melanin production begins by oxidation of tyrosine to dopaquinone, which is catalyzed by tyrosinase (TYR). The tyrosinase-associated protein-1 (TRP-1) and TRP-2 or dopachrome tautomerase also play an important role in all eumelanin-producing reactions [61].
）催化。酪氨酸酶相关蛋白-1（TRP-1）和TRP-2或多巴色素互变异构酶在所有真黑素生成反应中也起重要作用[157]。
Kang et al. [62] extracted and isolated five kinds of polyphenols from 等[158]从Ecklonia stolonifera. 中提取并分离了5种多酚。其中，间苯呋喃酚Among them, phlorofucofuroeckol A could significantly inhibit the activity of tyrosinase. 能显著抑制酪氨酸酶的活性。从褐藻Eisenia arborea phenols isolated from the polyphenolic compounds of the brown alga Ecklonia cava can significantly inhibit tyrosinase activity and prevent the formation and accumulation of melanin. Further research found that 974-A, phlorofucofuroeckol-A and eckol, isolated from 的多酚化合物中分离出的Ecklonia stolonifera Okamursenia arborea, reduced the cellular melanin content and tyrosinase activity, and downregulated the expression of melanogenesis enzymes including tyrosinase, tyrosinase酚类可以显着抑制酪氨酸酶活性并阻止黑色素的形成和积累。进一步研究发现，从冈村埃克洛氏菌中分离出的974-A、根腍呋喃-related protein (A和依克可降低细胞黑色素含量和酪氨酸酶活性，并下调B16F10黑色素瘤细胞中黑色素生成酶（包括酪氨酸酶、酪氨酸酶相关蛋白（TRP)-1 and TRP-2 in B16F10 melanoma cells [63]. These compounds also effectively scavenged radicals at the cellular level.
）-1和TRP-2）的表达[81]。这些化合物还有效地清除了细胞水平上的自由基。
3.2. Treatment of Atopic Dermatitis特应性皮炎的治疗
When the body is attacked by harmful stimuli or pathogens, the body’s immune system initiates an inflammatory response to remove the harmful substances and protect itself from harm. 当身体受到有害刺激或病原体的攻击时，身体的免疫系统会启动炎症反应，以去除有害物质并保护自己免受伤害。Atopic dermatitis (AD) is a cutaneous manifestation of a systemic disorder that can lead to asthma, food allergies and allergic rhinitis [64].
是一种全身性疾病的皮肤表现，可导致哮喘、食物过敏和过敏性鼻炎[159]。
Kim et al. [65] studied the activity of kombu ethanolic crude extract and found that the purified eckol can downregulate the expression of pro-inflammatory factors, tumor necrosis factor and two interleukins in mouse macrophage leukemia cells, confirming that brown algae polyphenol compounds have good anti-inflammatory activity and can be used to treat inflammation. A brand-new phlorotannin was isolated from Ecklonia kurome Okam, and the in vitro study of phlorofucofuroeckol-B on rat basophilic leukemia (等[160]研究了海带乙醇粗提物的活性，发现纯化的埃科尔可以下调小鼠巨噬细胞白血病细胞中促炎因子、肿瘤坏死因子和两种白细胞介素的表达，证实褐藻多酚化合物具有良好的抗炎活性，可用于治疗炎症。从黑叶埃克洛尼亚根冈分离出一种全新的根皮单宁，对大鼠嗜碱性粒细胞白血病（RBL)）-2H3 cells confirmed that this tannin is able to inhibit histamine release, thus guaranteeing anti-allergic properties [66].
细胞的间苯单酚-B的体外研究证实，这种单宁能够抑制组胺释放，从而保证抗过敏特性[161]。
3.3. Matrix Metalloproteinase Inhibitors基质金属蛋白酶抑制剂
基质金属蛋白酶（Matrix metalloproteinases (MMPs) are able to digest extracellular matrix components such as collagen, proteoglycans, fibronectin and laminin in vitro and in vivo. In particular, gelatinase, which effectively cuts collagen types IV and V, can degrade collagen and elastic fibers, resulting in loss of skin elasticity, promoting wrinkle formation and accelerating aging. Some studies have suggested that the effectiveness of the dieckol in downregulating the expression of MMPs preventing the cellular invasion. For example, dieckol treatment in ）能够在体外和体内消化细胞外基质成分，如胶原蛋白、蛋白聚糖、纤连蛋白和层粘连蛋白。特别是明胶酶，有效切割IV型和V型胶原蛋白，会降解胶原蛋白和弹性纤维，导致皮肤失去弹性，促进皱纹形成，加速衰老。一些研究表明，二醇在下调MMP表达以防止细胞入侵方面的有效性。例如，HT-1080 cells has reduced the intracellular ROS levels, inhibited the activation of Rac1 along with expression of focal adhesion kinase (FAK) and prevented the expressions of MMP-2, MMP-9 and 细胞中的dieckol处理降低了细胞内ROS水平，抑制了Rac1的活化以及粘附激酶（FAK）的表达，并阻止了MMP-2、MMP-9和MMP-13 [67].
Two phlorotannins, isolated from methanolic extracts of the marine brown alga, have been reported to inhibit the protein and gene expression levels of 的表达[162]。
据报道，从海洋褐藻甲醇提取物中分离出的两种根皮单宁可抑制人骨肉瘤细胞（MG-63）中MMP-1, 、MMP-3 and 和MMP-13 in human osteosarcoma cells (MG-63) [68]. 的蛋白质和基因表达水平[163]。从海带属中分离出的Dieckol and 和Eckol, isolated from Laminaria spp, inhibited the expression of 抑制了MMP-1 in human dermal fibroblasts [69]. These results suggested the phlorotannin could promote cell differentiation, attenuate 在人真皮成纤维细胞中的表达[164]。这些结果表明，根皮单宁可以促进细胞分化，减弱MMP-1, ，MMP-3 and 和MMP-13 expressions, and inflammatory responses via the MAPK pathway in chronic articular diseases.
的表达，并通过MAPK途径在慢性关节疾病中引起炎症反应。
3.4. As UV Sunscreens作为紫外线防晒霜
Under ultraviolet radiation, the human body can produce a variety of effects, such as 在紫外线辐射下，人体可产生多种作用，如DNA damage, inhibition of 损伤、抑制DNA replication or mutations, photosynthetic apparatus impairment, decrease in 复制或突变、光合器具受损、CO降低等。2-fixation, production of (固定，生产（ROS) [70]. Meanwhile, a decrease in the degree of photo-inhibition is commonly observed in brown algae. Such an effect may be explained either by activation of the antioxidative response, or by the formation of ）[165]。同时，在褐藻中通常观察到光抑制程度的降低。这种作用可以通过抗氧化反应的激活，或通过UV-screening compounds [71] and an increase in the activity of repairing enzymes. Phlorotannins are able to absorb 筛选化合物的形成[166]和修复酶活性的增加来解释。间苯单宁能够吸收紫外线辐射，主要是UV radiation, mainly UV-C and partly UV-B, with maxima at 195 nm and 265 nm making them good candidates for UV protection [72][73].
，部分吸收UV-B，最大值为195nm和265nm，因此非常适合紫外线防护[167，168]。
Gómez et al. [74] found that the induction of phlorotannins during UV exposure can alleviate the inhibition of photosynthesis and 等人[169]发现，在紫外线照射期间诱导根皮单宁可以减轻海带对光合作用的抑制和DNA damage in the kelp Lessonia nigrescens, two major detrimental effects of UV. Of course, the use of phlorotannins as a sunscreen is not only due to the anti-ultraviolet radiation effect, which requires antioxidant, anti-inflammatory and antibacterial effects to work synergistically. The ethyl acetate fractions that were isolated from the brown alga 损伤，这是紫外线的两大有害作用。当然，使用间苯单宁作为防晒霜不仅仅是由于抗紫外线辐射作用，这需要抗氧化、抗炎和抗菌作用协同作用。从褐藻Polycladia myrica have a greater ability to inhibit free radicals as well as inhibit the growth of Gram-positive bacteria. 中分离的乙酸乙酯组分具有更大的抑制自由基以及抑制革兰氏阳性细菌生长的能力。Soleimani et al. [75] used the ethyl acetate fraction (as a biofilter) at a concentration of 等人[170]使用浓度为5% as 的乙酸乙酯级分（作为生物过滤器）作为F3 and studied its sun protection efficacy, physical properties and stability. It turned out that the formulation F3 with ，并研究了其防晒功效，物理性能和稳定性。事实证明，SPF = 31.8 ± 4.7, UVA/UVB ratio ，UVA / UVB比率= 0.98, showed excellent UVR protection, compared with commercial sunscreen (的配方F3与商业防晒霜相比表现出优异的UVR保护（SPF = 29.76 ± 5.5, UVA/UVB ratio ± 5.5，UVA / UVB比率= 0.95). During stability studies, cream was formulated with a 5% fraction of brown algae without changes in appearance and pH.
）。在稳定性研究期间，乳膏由5%的褐藻配制而成，外观和pH值没有变化。
