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-π interactions) [97,98]. 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 [99]. They can interact with several receptors, regulate signal transduction, regulate enzyme activity, inactivate microorganisms and cross-link biological macromolecules [100], 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 [101].

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 [102]. 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.

Excessive oxidative stress can cause oxidative damage to intracellular biological macromolecules, promote abnormal gene expression and DNA structural changes and block vital signaling pathways between cells [107]. Brown algae polyphenols have good anticancer activity, and their mechanism of action is mainly manifested either directly as a pro-apoptotic, antiproliferative, anti-metastatic or anti-angiogenic agent, or indirectly by inhibiting the oxidative-stress inflammatory network closely related to tumorigenesis [108]. 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-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. [109] found that among three different seaweeds, Fucus evanescens, Laminaria cichorioides and Costaria costata, the former with 60% ethanol extracts have highest content of polyphenols (10.1% dry matter), showed the strongest inhibitory effect on 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 [89]. According to the work of Ahn et al. [110], carried out in xenograft mice models implanted with SKOV3 ovarian cancer cells, the oral administration 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. Dieckol, derived from edible brown alga Ecklonia cava, can significantly enhance the inhibition of tumor growth by cisplatin with lower weight loss and kidney damage in a mouse model [111]. It also indicated that brown algae phlorotannins may improve the efficacy of platinum drugs for ovarian cancer by enhancing cancer cell apoptosis via the ROS/Akt/NFκB pathway and reduce nephrotoxicity by protecting against normal kidney cell damage.

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 [112,113,114]. 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 (CNS)-related enzymes (acetylcholinesterase and butyrylcholinesterase, monoaminoxidase, β-secretase, tyrosinase); Regulation of neuronal receptors; Regulation of the signaling pathways and neuroinflammation associated with oxidative stress-mediated neuronal cell death [2].

Yang et al. [115] 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 5XFAD mouse models was alleviated. After oral administration of it, a significant decrease in the number of Aβ plaques and the level of the 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 (BBB) that separates the circulating blood from the brain extracellular fluid. Phlorotannin’s action through the BBB on gamma aminobutyric acid type A (GABAA)-benzodiazepine receptors has been demonstrated. Dieckol [116] and eckol [117] have been effectively shown to successfully penetrate the brain by the BBB via still unknown transportation mechanisms.

Polyphenolic compounds have a universal inhibitory effect on microorganisms [102]. 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 (ROS) production and trigger early apoptosis, leading to activation of the CaMCA1 gene and destruction of cell membranes in Candida albicans. These inhibitory effects reflect the potential of phlorotannins as a novel antifungal drug [44, 118,119].

Lopes et al. [120] crushed the dried Fucus spiralis Linnaeus, degreased with n-hexane and extracted with acetone: water (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 MIC values of phlorotannins for these fungi range from 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.

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, Scagassum, Laminaria japonica, Fucus vesiculosus and Hizikia fusifarme contain blood pressure-lowering active substances [121].

Dieckol isolated from the ethanol extract of Kombu is a non-competitive inhibitor against ACE I that induces the production of nitric oxide (NO) in EA.hy926 cells and has no cytotoxic effect [85]. Ko et al. [122] extracted 6,6’-bisphenols from the Ecklonia cava and studied its biological activity, finding that 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 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.

近年来，随着海连、羽扇、白藻等褐藻中活性成分的分离鉴定，证明大多数褐藻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-淀粉酶、α-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]。

从埃克洛尼亚的甲醇提取物中分离的根皮单宁对α-葡萄糖苷酶具有抑制活性，这归因于根唑仑素A、地科尔和7-根际醇的存在[125]。Lee等[126]以链脲佐菌素诱导的糖尿病小鼠为模型，从Ecklonia腔中提取根皮单宁，喂食后，在0、30、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小时血糖水平（对照：254.4±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和Abu-ghannam[128]发现，通过临床试验，每日补充Undaria pinnatifida可以平衡2型糖尿病患者的血糖水平。

一项为期24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损伤和抗氧化活性的影响[105]。共有80名参与者（BMI单位：kg / m²≥ 25 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。

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）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 SARS-CoV 抑制活性。此外，dieckol 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 与蛋白质具有很高的缔合率，并与 SARS-CoV 3CL（Cys145 和 His41）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 等人 [78] 评估了根单宁作为 SARS-CoV-2 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A和B，岩藻二苯酚G，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COVID-19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）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犬肾（MDCK）通透性。

大多数根皮单宁代谢物是在晚期时间点（6-24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（I.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等人[134]研究了食用12周的E. cava多酚提取物（seapolynol）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 30 公斤/米².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-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。

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]。

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具有抑制HMG-CoA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。

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）。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]。

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。

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。

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 μg/mL）下抑制了33%的Ciona Savignyi和27%的Halocynthia roretzi的变质作用。这些发现表明，间苯单宁可以作为防污剂，而不会对其他生物造成损害[75]。

The larvicidal activities of phlorotannins in mosquitoes reported by Ravikumar et al. [154] and Manilal et al. [155] suggest that they may be effective repellents. Phlorotannins have an effect on the larvae of marine invertebrates [156], 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.

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 [157].

Kang et al. [158] extracted and isolated five kinds of polyphenols from Ecklonia stolonifera. Among them, phlorofucofuroeckol A could significantly inhibit the activity of tyrosinase. 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 Ecklonia stolonifera Okamura, reduced the cellular melanin content and tyrosinase activity, and downregulated the expression of melanogenesis enzymes including tyrosinase, tyrosinase-related protein (TRP)-1 and TRP-2 in B16F10 melanoma cells [81]. These compounds also effectively scavenged radicals at the cellular level.

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. Atopic dermatitis (AD) is a cutaneous manifestation of a systemic disorder that can lead to asthma, food allergies and allergic rhinitis [159].

Kim et al. [160] 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 (RBL)-2H3 cells confirmed that this tannin is able to inhibit histamine release, thus guaranteeing anti-allergic properties [161].

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 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 MMP-13 [162].

Two phlorotannins, isolated from methanolic extracts of the marine brown alga, have been reported to inhibit the protein and gene expression levels of MMP-1, MMP-3 and MMP-13 in human osteosarcoma cells (MG-63) [163]. Dieckol and Eckol, isolated from Laminaria spp, inhibited the expression of MMP-1 in human dermal fibroblasts [164]. These results suggested the phlorotannin could promote cell differentiation, attenuate MMP-1, MMP-3 and MMP-13 expressions, and inflammatory responses via the MAPK pathway in chronic articular diseases.

Under ultraviolet radiation, the human body can produce a variety of effects, such as DNA damage, inhibition of DNA replication or mutations, photosynthetic apparatus impairment, decrease in CO₂-fixation, production of (ROS) [165]. 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 UV-screening compounds [166] and an increase in the activity of repairing enzymes. Phlorotannins are able to absorb UV radiation, mainly UV-C and partly UV-B, with maxima at 195 nm and 265 nm making them good candidates for UV protection [167,168].

Gómez et al. [169] found that the induction of phlorotannins during UV exposure can alleviate the inhibition of photosynthesis and 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 Polycladia myrica have a greater ability to inhibit free radicals as well as inhibit the growth of Gram-positive bacteria. Soleimani et al. [170] used the ethyl acetate fraction (as a biofilter) at a concentration of 5% as F3 and studied its sun protection efficacy, physical properties and stability. It turned out that the formulation F3 with SPF = 31.8 ± 4.7, UVA/UVB ratio = 0.98, showed excellent UVR protection, compared with commercial sunscreen (SPF = 29.76 ± 5.5, UVA/UVB ratio = 0.95). During stability studies, cream was formulated with a 5% fraction of brown algae without changes in appearance and pH.