Table 2.

Different types of phlorotannins exhibiting anticancer, anti-inflammatory, antidiabetic, antioxidant, anti-obesity, anti-adipogenesis, and other biological activities.

Pure Phlorotannin or Extracts	Sources	Purification Methodology	Biological Activity	Active Concentration	Types of the Testing Method	Action Mechanism	Reference
Anticancer
6,6′-Bieckol 8,8-Bieckol Dieckol 7-Phloroeckol Phlorofucofuroeckol	Ecklonia cava	ND	Ovarian cancer cells undergo apoptosis	IC50 84.3 and 99.6 µg/mL against A2780 and SKOV3 cells for ethanolic extract IC50 77.31 and 92.7 µg/mL against A2780 and SKOV3 cells for dieckol IC50 77.31 to 137.77 and 96.3 to >200 µg/mL against A2780 and SKOV3 cells for others	PI staining MTT assay PI and Annexin double staining Western blot analysis and flow cytometry and SKOV3 tumor xenograft model	Inhibited tumor xenograft growth Cytotoxicity effect on ovarian cancer cells (A2780 and SKOV3) Caused mitochondria disfunction Suppressed the levels of anti-apoptosis protein Induced ROS Reversed the caspase activation	[78]
Phloroglucinol derivatives Dioxynodehydroeckol 1-(3′,5′-Dihydroxyphenoxy)-7-(2″,4″,6-trihydroxyphenoxy)-2,4,9-trihydroxydibenzo-1,4-dioxin	E. cava	Silica-gel column chromatography	Human breast cancer cells	At 100 µM, it inhibited MCF-7 cells growth by 64% Inhibited proliferation of MDA-MB-231 cells 55% at 100 µM	Cell proliferation assay	Anti-proliferative activity on MCF-7 cancer cells Downregulated NF-κB and depended on activated genes Induced caspase activity Induced the cleavage of DNA repair enzyme Induced pro-apoptotic gene Suppressed anti-apoptotic gene	[79]
Phloroglucinol	Brown seaweeds	ND	MDA-MB231 breast cancer cells	IC50 50 µM of migratory and invasive ability of MDA-MB231 breast cancer cells	Western blot analysis Activated RAS affinity precipitation assay Invasion and migration assay	SLUG was suppressed by inhibiting P13K/AKT and RAS/RAF-1/ERK signaling Reduced cancer cell’s metastatic ability	[80]
Phloroglucinol	Seaweeds	ND	Human colon cancer cells HT-29	12.5 µg/mL caused fragmented nuclei and cell shrinkage	Western blot analysis Cell cycle analysis mRNA expression analysis 4′-6′-Diamidino-2-phenylindole staining assay	Downregulated the expression of Ras, Raf, and mitogen-activated protein kinase Downregulated the phosphorylation of the extracellular-signal-regulated kinase Decreased mammalian target of rapamycin and expression of its downstream effectors p70S6 kinase Decreased elF4b and RPS6 translation initiation factor	[135]
Phlorotannins	Cystoseira sedoides	Reversed-phase column chromatography	MCF-7 cells (human breast cancer cells)	In MCF-7 cells, the IC50 for inducing apoptosis was 78 µg/mL	Double Annexin V-FITC/PI test	Prevented spheroid growth	[82]
Dieckol	E. cava	Sephadex LH-20 column chromatography	Protective efficacy against N-nitrosdiethylamine -induced rat hepatocarcinogenesis	Alkaline phosphatase, lactate dehydrogenase, transaminase, gamma-glutamyl transferase, total bilirubin, and a-fetoprotein activities increased in NDEA-induced rats given dieckol water (10–40 mg/kg body weight) for 15 weeks	Serum marker enzymes analysis	It prevents hepatic cell damage and lipid peroxidation NDEA-induced hepatocarcinogenesis enhances the enzymatic and non-enzymatic antioxidant defense system	[83]
Isololiolide	C. tamariscifolia	Reverse phase preparative HPLC	Anti-proliferative activity	IC50 32.36 µM of cytotoxic activity against gastric cancer cells IC50 23.59 µM of cytotoxic activity against colon cancer cell line IC50 13.15 µM of cytotoxic activity against human hepatocellular carcinoma cells	MTT colorimetric assay	Expression of proteins in the apoptotic cascade Induced apoptosis through the modulation of apoptosis-related proteins.	[136]
Anti-inflammatory
Ethyl acetate fraction of methanolic extraction Phloroglucinol (PG) Phlorofucofuroeckol A (PFA) Eckol (EK) 7-Phloroeckol (7-PE) Dieckol (DE)	Eisenia bicyclis	Chromatography on silica gel column	Cell viability and NO production (LPS-induced RAW264.7 cells)	>10 µg/mL cytotoxicity for PG and PFA 24.5% and 66.2% inhibition of NO production for PG and PFA IC50 52.86, 51.42, and 26.87 µg/mL for EK, DE, 7-PE	MTT assay	Inhibited NF-κB -related inflammatory gene expression via ROS inhibition Inhibited LPS-induced nitric oxide and butyl hydroperoxide-induced ROS production	[64]
Phloroglucinol	E. cava	ND	Inhibition of oxidative stress and inflammation	Inhibition of protein oxidation (90% at 10 µM) Inhibition of TNF-α, IL-1β (30% at 10 µM) Inhibition of PGE2 (40% at 10 µM)	MTT assay Membrane protein oxidation assay Enzyme immunoassay Western blot analysis	Inhibited oxidative stress Inhibited the production of IL-6, TNF-α, IL-1β, and PGE2 Matrix metalloproteinase expression was reduced	[66]
Phlorotannins	Bifurcaria bifurcata	Reversed-phase column chromatography	Cytotoxic effect on ATDC-5 mouse model cell lines	50% inhibition of cell growth in ATDC-5 cells at 100 µM	MTT assay	ND	[68]
Phlorotannins	Padina tetrastromatica	Reversed-phase column chromatography	Effect on THP-1 cell viability	From 1.5 to 50.0 µg/mL	MTT assay	Anti-MRSA potential Enhances the high-glucose-induced pro-MMP-9 expression	[69]
Phloroglucinol	Brown algae	ND	Anti-inflammatory effect and oxidative stress on RAW264.7 and HT1080 cells	From 1 to 100 µM	MTT assay	Inhibitory effects on oxidative stress and the production of inflammatory mediators such as IL-6, TNF-a, IL-1β, and PGE2 in RAW264.7 cells stimulated by LPS Decreased the expression of matrix metalloproteinase in HT1080 cells	[66]
Phlorotannins	Fucus guiry F. serratus F. sprialis F. vesiculosus-wild F. vesiculous-aquaculture	Aqueous acetone extraction	Anti-inflammatory and toxicity capability in RAW 264.7 macrophages and cell-free systems	IC50 82.10, 110.16, 362.42, 364.84, > 500 μg DE/mL for LOX inhibition, respectively IC50 451.91, 1214.73, 801.97, 1330.61, 2072.32 μg DE/mL for NO scavenging, respectively IC25 97.73, 77.04, 95.86, 56.52, 317.41 μg DE/mL for NO reduction, respectively Nontoxic at 31.25–500 μg/mL in RAW 264.7 macrophages stimulated with bacterial LPS	MTT assay	Function in inflammatory conditions, acting on both enzymatic and non-enzymatic inflammatory targets	[65]
Phlorofucofuroeckol B (PFF-B)	E. stolonifera	High-performance chromatography	PFF-B inhibits the generation of inflammatory mediators induced by LPS	Decreased secretion of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6 Decreased expression of pro-inflammatory proteins such as COX-2 and inducible NO synthase	MTS assay NF-κB promoter/luciferase assay	By limiting the breakdown of the inhibitor κb-α, the activation of nuclear factor kappaB was prevented. Inhibited the phosphorylation of Akt, ERK, and JNK	[70]
6,6′-Bieckol	E. cava	ND	LPS-stimulated macrophage RAW 264.7 cells have anti-inflammatory effects	Inhibited NO and PGE2 production at concentrations of 100, 200 μM Suppressed the LPS-induced expression of COX-2 and inducible-NOS and at the mRNA and protein levels TNF-α and IL-6 mRNA expression were reduced	MTT assay PGE2 assay Chromatin immunoprecipitation assay	Downregulation of COX-2, iNOS, and pro-inflammatory cytokines in LPS-stimulated macrophages via the NF-κB pathway	[71]
Phlorofucofuroeckol B	Myagropsis myagroides	High-performance chromatography	Anti-inflammatory activity	Inhibited LPS-induced PGE2 and NO production Inhibited COX-2 and iNOS Pro-inflammatory cytokines were inhibited, as well as NF-κB activation and translocation	MTS assay Transient transfection and luciferase assay	In LPS-stimulated macrophage cells, the NF-κB pathway was inhibited by inhibiting the phosphorylation of ERKs and Akt	[67]
Antidiabetic
Ethyl acetate fraction of methanolic extraction Dioxynodehydroeckol (DDE) Fucofuroeckol (FFE)	E. bicyclis	Chromatography and nuclear magnetic resonance	Antidiabetic activity	IC50 131.34 nmol/L for α-glucosidase and 42.91 µmol/L for α-amylase for FFE IC50 93.33 nmol/L for α-glucosidase and 472.7 µmol/L for α-amylase for DDE	Enzymatic inhibitory assay	Inhibition of α-amylase and α-glucosidase enzyme activities	[106]
Phlorofucofuroeckol Dieckol 6-6′-Bieckol 7-Phloroeckol Fucodiphloroetho	E. cava	Column chromatography using silica gel	antidiabetic activity	IC50 10.75 to 49.49 µmol/mL for α-glucosidase and >500 to 124.98 µmol/L for α-amylase	Enzymatic inhibitory assay	Inhibition of α-amylase and α-glucosidase enzymes activities	[107]
Phlorotannins	C. compressa	UPLC-MS/MS	Antidiabetic activity	After four weeks of diabetes induction, diabetics were treated with 60 mg/kg of phlorotannin extract.	MTT assay	Reduced serum glucose, malondialdehyde, glucosidase, and α-amylase activity in the liver Reduced damage in pancreatic β cells	[108]
Ethylacetate fraction of acetone extract	F. vesiculosus	Mass spectroscopy (UHPLC-MS)	Antidiabetic and anti-obesity activity	IC50 for α-amylase 2.8 µg/mL IC50 for α-glucosidase 0.82 µg/mL IC50 for pancreatic lipase 0.82 µg/mL	α-amylase, α-glucosidase, pancreatic lipase inhibitory assay	Inhibited α-amylase, α-glucosidase, and pancreatic lipase enzymes Delayed carbohydrates and lipid digestion	[109]
Ishophloroglucin A	Ishige okamurae	Semipreparative HPLC column	Anti-α-glucosidase activity	IC50 value of 54.97 µM in α-glucosidase inhibition	α-Glucosidase inhibitory assay	Inhibited α-glucosidase	[110]
Phlorofucofuroeckol A	E. cava	Electrospray ionization-multistage tandem mass spectrometry and HPLC	Antidiabetic activity	IC50 for α-amylase 6.34 µM IC50 for α-glucosidase 19.52 µM	α-Glucosidase inhibitory assay α-Amylase inhibitory assay	Inhibition of α-amylase and α-glucosidase enzymes activities	[111]
Dieckol	E. cava	Reversed-phase HPLC	Antidiabetic activity	Dieckol administration reduced blood glucose levels, serum insulin levels, and body weight Increased activity of anti-oxidant enzymes in liver tissues, including superoxide dismutase, catalase, and glutathione peroxidase	Serum glucose content reduced Lipid peroxidation production Catalase and superoxide dismutase activities	Activates both the AMPK and PKB signaling cascades	[112]
Antioxidant
Dichloromethane fraction of methanolic extraction	C. trinodis (Forsskal) C. Agardh	Silica-gel column chromatography	Antioxidant activity	69.62% radical scavenging activity	DPPH radical scavenging	ND	[89]
Dichloromethane fraction of ethanolic extraction 974-A 974B Phloroglucinol Dieckol	E. curome	Sequential chromatography on two reverse phase column	Antioxidant activity	IC50 10, 11, 110, 10 µM respectively	DPPH radical scavenging	Reduced intracellular reactive oxygen species	[90]
Ethylacetate fraction of methanolic extract Phloroglucinol Eckol Dieckol	E. cava	Sephadex LH-20 column chromatography	Antioxidant activity	90% radical scavenging activity for eckol at 0.25 to 1 mg/mL 100% hydroxyl radical scavenging activity for dieckol at 0.25 mg/mL 90% alkyl radical scavenging activity for eckol at 0.05 mg/mL 68.96% to 50% DNA damage values for all three at 25 µg/mL	DPPH radical assay Hydroxyl radical assay Alkyl radical assay Superoxide radical assay Comet assay (Protecting effects against H2O2-mediate DNA damage	Inhibited free radical activities Damaged DNA	[91]
Ethanolic extract Phlorotannins	Sargassum inggoldianm	Matrix-assisted laser desorption ionization time-of-flight mass spectroscopy	Antioxidant activity	IC50 1.0 µg/mL	Electron spin resonance spectrometry	Showed superoxide anion radical scavenging activity	[92]
Phlorotannins	S. dupplicatum	Sephadex LH-20 column chromatography	Antioxidant activity	Total antioxidant activity 11.17 ± 0.28 mg ascorbic acid equivalent/g DW Reducing power activity by 11.09 ± 0.24 mg FeSO4 equivalent/g DW	Antioxidant activity Reducing power activity	ND	[93]
Phlorofucofuroeckol-A	E. cava	Centrifugal partition chromatography	Antioxidant activity	Scavenging activity against alkyl radicals, with an IC50 value of 3.9 µM With an IC50 value of 21.4 µM, it has a scavenging action against hydroxyl radicals With an IC50 value of 10.3 µM, it has a scavenging action against DPPH radicals	Assay for alkyl radical scavenging capacity Assay for hydroxyl radical scavenging capacity DPPH assay	Antioxidant and lipid peroxidation protection Malondialdehyde inhibition in AAPH-stimulated Vero cells	[94]
Dieckol Eckol Eckstolonol Phloroglucinol Triphloroethol A	E. cava	HPLC	Neuroprotective against H2O2-induced cellular damage in HT22 neuronal cells from the murine hippocampus	ROS levels were reduced to 75.22%, 69%, 67.32%, 77.63%, 77.73%, respectively (treatment of H2O2-treated cells at a concentration of 50 M) The apoptotic sub-G1 DNA content was reduced to 9.55%, 13.03%, 5.55%, 6.61%, 3.03%, respectively (pre-treatment with 50 M phlorotannins)	Scavenging efficacy on ROS production Neuroprotective effects in H2O2-treated HT22 cells	Remove intracellular ROS and inhibit ROS accumulation Inhibited H2O2-induced Ca2+ release	[96]
Dieckol Eckol Eckstolonol Phloroglucinol Triphloroethol A	E. cava	Sephadex LH-20 column chromatography	The ability of phlorotannins to scavenge ROS in AAPH-induced zebrafish embryos	Reduced intracellular ROS buildup to DCF-DA intensity of 1568, 2346, 1703, 1540, and 2262, respectively (50 µM phlorotannins + 25 mM AAPH)	ROS generation in AAPH-induced zebrafish embryos	Antioxidant efficacy against AAPH-mediated toxicity	[95]
Anti-obesity
Ethylacetate fraction of methanol extraction 6-6′-Bieckol Dieckol Phlorofucofuroeckol A	E. cava	Sephadex LH-20 column chromatography	Inhibition of adipogenesis	Inhibited lipid accumulation 60%, 40% 20% at 100 µL respectively	Oil-Red O staining method	Downregulated adipogenic specific genes (SREBP-1, C/EBPα, FABP4, and PPARγ)	[116]
Ethylacetate fraction of ethanolic extraction Dioxynodehydroeckol	E. cava	Silica-gel column chromatography	Inhibition of adipogenesis	Inhibited adipogenesis 20 µM	Oil-Red O staining method	Reduced lipid accumulation Downregulated the expression of adipogenic specific genes of 3T3-L1 (C/EBPα, SREBP1, and PPARγ) Activated and modulated AMPK signaling pathway	[113]
Diethyl ether fraction of methanolic extract Dieckol Eckol	E. cava	Sephadex LH-20 column chromatography	Inhibition of melanogenesis (UV-B radiation-induced cell damage protection effect)	92.7% (dieckol) and 62.4% (eckol) inhibitory effect on tyrosinase at 100 µM	Tyrosinase inhibition assay DCFH-DA, MTT, comet assay	Inhibited tyrosinase Inhibited melamine syntheses	[114]
Anti-adipogenesis
Ethylacetate fraction of methanolic extraction Phloroglucinol Eckol Dieckol Dioxynodehydroeckol Phlorofucofuroeckol A	E. stolonifera	Sephadex LH-20 column chromatography	Inhibition of adipogenesis	Inhibited adipogenesis (12.5–100 µM)	Oil Red O staining	Downregulated adipogenic specific genes of 3T3-L1 (C/EBPα and PPARγ)	[100]
Dieckol	Laminaria japonica	Silica gel resin absorption	Anti-fatty liver activity	Body weight gain, plasma lipid profiles, visceral fat index, liver index, and hepatic fat deposition were improved in high-fat diet mice given a dieckol-enriched extract (50 mg/kg/day) for four weeks	Histopathological analysis	Advantageous effects on hepatic lipid metabolism Stimulation of hepatic fatty acid β-oxidation	[115]
Dieckol	E. cava	Reverse-phase high-performance liquid chromatography	Inhibitory effect on adipogenesis	Inhibition of adipogenesis Peroxisome proliferator-activated receptor, CCAAT/enhancer-binding proteins, fatty acid-binding protein, and SREBP1 expression were all reduced	MTT assay	Activated AMP-activated protein kinase	[116]
Other biological activities
Ethyl acetate fraction of methanolic extract Phloroglucinol	E. cava	Sephadex LH-20 column chromatography	Cytoprotective effect against oxidative stress-induced cell damage in (V79-4) Chinese hamster lung fibroblast	65% DPPH radical scavenging activity at 10 µg/mL 70% H2O2 scavenging activity at 10 µg/mL 26% hydroxy radicals scavenging activity at 10 µg/mL 73% Intracellular reactive oxygen scavenging activity at 10 µg/mL	Radical scavenging activity assay MTT assay Western blot analysis	Scavenge 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical Scavenge H2O2, hydroxy radicals Prevented lipid peroxidation Reduced intracellular reactive oxygen species Increased the activity of catalase Increased phosphorylation of the extracellular signal-regulated kinase	[137]
Ethyl acetate fraction of methanolic extract Phloroglucinol	E. cava	Sephadex LH-20 column chromatography	Radioprotective effect of cells against γ-ray radiation-induced oxidative damage	Phloroglucinol-treated cells reduced irradiation DNA damage by 27% Cell survival rose to 66% in irradiated cells at 10 µg/mL phloroglucinol	Laser scanning microscopy Colorimetric assay Lipid peroxidation assay Western blot analysis Comet assay	Reduced the amount of radiation-induced intracellular ROS Reduced cellular component (lipid, DNA, and protein) damage Reduced the radiation-induced loss of mitochondrial membrane action potential Reduced the active levels of caspase-3 and 9	[138]
Phloroglucinol	Seaweeds	ND	UVB-induced photoaging of human HaCaT keratinocytes	10 µg/mL protected HaCaT keratinocytes against UVB-induced cytotoxicity 10 µg/mL inhibited the accumulation of UVB-induced MMP-1 mRNA and protein at 48 h	UV/visible light absorption analysis Intracellular ROS measurement Western blot analysis Human active MMP-1 Fluorokine E fluorescent assay Chromatin immunoprecipitation assay	Upregulated MMP-1 mRNA and protein activity Augmented intracellular Ca2+ level Phosphorylation of mitogen-activated protein kinases Enhanced the activator protein-1 (AP-1) binding to the MMP-1 promotor	[139]
Phlorotannins	E. radiata	High-performance counter-current chromatography	Neuroprotective activity	In neuronal PC-12 cells, it was nontoxic up to 50 µM Cholinesterase inhibitory activity at IC50 value of 41 µM	MTT assay Acetylcholinesterase inhibitory assay	Elicited neuroprotective activity against amyloid β protein, Aβ1–42 Inhibited Aβ1–42 aggregation, AChE activity, and ROS formation in PC-12 cells Neuroprotective effects through multiple pathways	[140]
Phlorotannins	E. cava	Sephadex LH-20 column chromatography	MG63 cell survival and calcium deposition on polycaprolactone (PCL/Ph) micro nanofibres	Increased cell survivability on PCL/Ph micro nanofibers as phlorotannin content increased Increased calcium mineralization on the PCL/Ph micro nanofibers after 14 days	MTT assay	Enhanced bone tissue growth	[116]
Dioxynodehydroeckol	E. cava	Silica-gel column chromatography	UVB-induced apoptosis prevention in human keratinocyte (HaCaT) cells	Reduced by 1.83% at 20 µM of DHE compared to 13.31% in cells exposed to UVB	Flowcytometry following Annexin V and PI labeling	ND	[141]
Dieckol	E. cava	Sephadex LH-20 with MeOH	Anti-proliferative and anti-angiogenic effect on EA. hy926 cell lines induced with vascular endothelial growth factor	Nontoxic up to 100 µM in EA. hy926 cells Inhibition activity of AP-N enzyme with an IC50 value of 52.80 µM Dieckol at the concentration of 10, 50, and 100 µM inhibited vascular endothelial growth factor-induced cell proliferation.	MTT assay Aminopeptidase-N enzyme assay Cell proliferation assay	Cell migration was inhibited by lowering the level of protein and gene expression of matrix metalloproteinases such as MMP-2 and -9	[142]